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23260763 | Pneumocystis jirovecii genotype associated with increased death rate of HIV-infected patients with pneumonia. | Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations have been associated with failure of sulfa prophylaxis; their effect on the outcome of patients with P. jirovecii pneumonia (PCP) remains controversial. P. jirovecii DHPS polymorphisms and genotypes were identified in 112 cases of PCP in 110 HIV-infected patients by using PCR single-strand conformation polymorphism. Of the 110 patients observed, 21 died; 18 of those deaths were attributed to PCP. Thirty-three percent of the PCP cases involved a P. jirovecii strain that had 1 or both DHPS mutations. The presence or absence of DHPS mutations had no effect on the PCP mortality rate within 1 month, whereas P.jirovecii type 7 and mechanical ventilation at PCP diagnosis were associated with an increased risk of death caused by PCP. Mechanical ventilation at PCP diagnosis was also associated with an increased risk of sulfa treatment failure at 5 days. |
23260762 | [When should request a stool culture?]. | A stool culture needs a medical prescription and is justified only in a case of clearly defined acute diarrhea. The clinical context must be suggestive of a bacterial etiology. The detection of the bacterial agents has to follow a well-defined strategy to optimize a rigorous prescription. Standardized stool culture is for patients treated in medical community practice and for patients hospitalized for less than 3 days. Clostridium difficile toxin testing is systematically performed in case of nosocomial diarrhea. Additional bacterial detections are limited to defined indications. |
23260759 | [Intestinal microbiota: from antibiotic-associated diarrhea to inflammatory bowel diseases]. | The intestinal microbiota is known to be composed by several hundred different bacterial species and is stable over time. Antibiotics intake induces a disturbance in the composition of intestinal microbiota which impairs its protective role against infection by pathogens. The presence of a large biomass of bacteria in the digestive tract exerts physiological effects with beneficial consequences for the host. Patients with inflammatory bowel diseases, exhibit an imbalance in the composition of intestinal microbiota called dysbiosis. |
23260751 | A comparison of the diagnostic performance of the ST/HR hysteresis with cardiopulmonary stress testing parameters in detecting exercise-induced myocardial ischemia. | Because ST segment depression has limited diagnostic performance at exercise electrocardiography (ECG), ST segment depression/heart rate (ST/HR) hysteresis and cardiopulmonary exercise test (CPET)-derived parameters have been proposed as alternatives to diagnose exercise-induced myocardial ischemia. We compared the diagnostic performance of such parameters. We studied 56 subjects (45 men, 11 women, age 59.7 ± 13.6 years) referred for suspected exercise-induced myocardial ischemia with an equivocal ECG exercise test. All subjects serially underwent CPET and a myocardial single-photon emission computerized tomography (SPECT) perfusion imaging (as the gold standard for ischemia). Maximum ST depression at peak exercise (ST-max), the ST/HR hysteresis, ΔVO2/ΔWR b-b1 slope, ΔVO2/ΔWR (aa1-bb1), VO2/HR flattening duration and other CPET parameters were derived in all subjects. On the basis of SPECT, 23 subjects (41%) were considered ischemic and 33 subjects (59%) non-ischemic. ST/HR hysteresis was higher (0.026 mV; 95% CI: 0.003 to 0.049 vs -0.016 mV; 95% CI: -0.031 to -0.001 mV) and ST-max was lower (-0.105 mV; 95% CI: -0.158 to -0.052 vs 0.032 mV; 95% CI: -0.001 to -0.066 mV) in ischemic vs non-ischemic subjects (P=0.004 and P=0.001, respectively). Among CPET parameters, ΔVO2/ΔWR b-b(1) slope was lower (9.4 ± 3.8) and ΔVO2/ΔWR (aa(1)-bb(1)) was higher (2.1 ± 2.6) in ischemic vs non-ischemic subjects (11.4 ± 2.3, P=0.005, and 1.1 ± 1.5, P=0.001, respectively). The ST/HR hysteresis had the highest area under the curve value, better (P<0.05) than any other parameters tested, thus showing the highest overall diagnostic performance. The ST/HR hysteresis is superior to CPET-derived parameters for detecting exercise-induced myocardial ischemia in patients with equivocal ECG exercise test results. |
23260750 | Supplemental intravenous n-3 fatty acids and n-3 fatty acid status and outcome in critically ill elderly patients in the ICU receiving enteral nutrition. | N-3 fatty acids (FA) may have benefits in ICU patients. The aims were to identify whether FA status is altered in critical illness and to evaluate the effect of supplemental intravenous n-3 FA on plasma FA status and clinical outcome in ICU patients receiving enteral nutrition. Enterally fed patients (n = 49; 60-80 years) were recruited in the first 48 h of ICU admission. Fifteen patients received n-3 FA emulsion (0.2 g/kg) over 6 h for 3 consecutive days, and 34 patients did not (control). Samples were collected before supplementation, and 24 and 72 h after the third infusion. Nineteen healthy elderly subjects were also studied; they gave a single blood sample. FA were measured in plasma phosphatidylcholine (PC). Critically ill patients had altered plasma PC FA compared with healthy elderly subjects. Surviving ICU patients had higher levels of docosahexaenoic acid and total n-3 FA and a lower ratio of n-6:n-3 FA in plasma PC than non-survivors. Infusion of n-3 FA increased eicosapentaenoic, docosahexaenoic and total n-3 FA, and decreased arachidonic and total n-6 FA and n-6:n-3 FA and arachidonic:eicosapentaenoic acid ratios. Gas exchange was enhanced 72 h after the third n-3 FA infusion (p = 0.001). Critically ill patients may have altered plasma FA profiles. A higher total n-3 FA and docosahexaenoic acid content in plasma PC is associated with survival and improved gas exchange. |
23260749 | Low compliance with dietary recommendations for food intake among adults. | To assess the adherence to the national dietary recommendations and to identify factors contributing to dietary compliance in Switzerland. Population-based cross-sectional study in Lausanne, Switzerland (CoLaus study), 2009-2012. Dietary intake was assessed using a validated food frequency questionnaire. Participants were dichotomized according to whether they followed the national recommendations for fruits, vegetables, meat, fish and dairy products. Data from 4371 participants (54% women, mean age ± SD: 57.6 ± 10.5 years) were analyzed. Compliance with the recommendations was low: only 39.4%, 7.1%, 61.3%, 66.4%, and 8.4% complied with the Swiss recommendations for fruit (≥2/day), vegetables (≥3/day), meat (≤5/week), fish (≥1/week) and dairy products (≥3/day), respectively. In multivariate analyses, gender, age, smoking status, Swiss-born status, education, being on a diet and body mass index were associated with dietary compliance, while no difference was found between women before and after menopause. Factors specifically associated with fruits, vegetables, meat, fish or dairy products recommendations were identified. The low degree of compliance with dietary recommendations calls for a continued effort to increase the population awareness of the importance of a healthy and balanced diet, especially for vegetables and dairy products. This study identified determinants that should guide this effort. |
23260748 | Education program on medical nutrition and length of stay of critically ill patients. | To evaluate the impact of a multifaceted nutritional educational intervention on the quality of nutritional therapy and clinical outcomes in critically ill patients. We conducted a prospective, non-blinded study with a non-contemporaneous control group at a 16-bed intensive care unit (ICU) at the Hospital das Clinicas, Department of Gastroenterology, University of Sao Paulo Medical School in Sao Paulo, Brazil. There were three phases. Phase 1: the quality of NT was evaluated in 50 newly admitted intensive care unit patients in a pre-educational program (Pre-EP). Phase 2: nutritional protocols were created and an education program was implemented. Phase 3: another 50 patients were enrolled and observed in a post-educational program (Post-EP) using phase 1 methodology. Nutritional Therapy practice was evaluated through nutritional assessments, adequacy of energy requirements, duration of fasting, and use of early enteral nutrition. Intensive care unit length of stay and hospital length of stay were measured as primary end-points. The pre-educational program and post-educational program groups did not differ in age, APACHE II score, gender, or nutritional assessment. The mean ± SD duration of fasting decreased (Pre-EP 3.8 ± 3.1 days vs. Post-EP: 2.2 ± 2.6 days; p = 0.002), the adequacy of nutritional therapy improved (Pre-EP 74.2% ± 33.3% vs. Post-EP 96.2% ± 23.8%; p < 0.001), and enteral nutrition was initiated earlier than 48 h more commonly (Pre-EP 24% vs. Post-E 60%; p = 0.001). Median intensive care unit length of stay decreased (Pre-EP: 18.5 days vs. Post-EP: 9.5 days; p < 0.001) although hospital length of stay did not. Implementing a multifaceted nutritional educational intervention could improve the quality of nutritional therapy and may decrease intensive care unit length of stay in critically ill patients. |
23260747 | Nutritional evaluation of rapeseed protein compared to soy protein for quality, plasma amino acids, and nitrogen balance--a randomized cross-over intervention study in humans. | Plant proteins such as rapeseed have received little attention for human nutrition due to their high level of antinutritive compounds. Today, newer technologies can eliminate such compounds. The present intervention study aimed to evaluate nutritional and physiological properties of two manufactured canola proteins with special focus on their bioavailability in humans. 28 healthy male subjects (ø 25 years) consumed 30.0 g protein (canola protein isolate--CPI, canola protein hydrolyzate--CPH or soy protein isolate--SPI) in a randomized, double-blind, cross-over study. Blood samples were regularly drawn over the 8-h postprandial period and a 24-h urine sample was collected. True digestibility of the canola proteins determined in a separate rat assay showed 93.3% for CPI and 97.3% for CPH. In humans, consumption of either 30.0 g canola protein or soy protein mixed in a drink led to significant increases in plasma amino acids after 62.3 and 83.6 min, respectively. While the CPH produced an earlier response compared to CPI and SPI, total amino acid response (AUC for 8 h) was comparable between all interventions. The nitrogen balance between the three proteins tested showed no statistical differences. High digestibility of rapeseed protein was found in rats. In humans, this is the first intervention study showing rapeseed protein (both isolate and hydrolyzate) as having a high nutritional quality and can be considered to be as efficient as soy protein for a postprandial amino acid response. This trial was registered at ClinicalTrials.gov Identifier: NCT01481584. |
23260733 | Towards a typology of rural responses to healthcare in Mexico, 1920-1960. | After the revolutionary conflicts of the 1910s, the Mexican state sought to bring peace to the country's obstreperous, rebellious and often downright unknown rural provinces through the establishment of a new social pact. Peasants were to embrace political loyalty, productivity, and secularization in return for land, education and healthcare. Success depended on multiple regional factors and even healthcare, often presented as a neutral, politically uncharged benefit, faced ample opposition. Using four examples, I seek to examine why certain regions embraced post-revolutionary healthcare, while others preferred to remain wedded to 'traditional' or Catholic medical institutions and practices. |
23260730 | Comparison of child obesity prevention and control content in mainstream and Spanish-language US parenting magazines. | Mass media coverage of child obesity is rising, paralleling the child obesity epidemic's growth, and there is evidence that parents seek parenting advice from media sources. Yet little to no research has examined the coverage of child obesity in parenting magazines or Spanish-language media. The purpose of this study was to use qualitative and quantitative content analysis methods to identify, quantify, and compare strategies for child obesity prevention and control presented in mainstream and Spanish-language US parenting magazines. Child obesity-related editorial content in 68 mainstream and 20 Spanish-language magazine issues published over 32 months was gathered. Magazine content was coded with a manual developed by refining themes from the sample and from an evidence-based child obesity prevention action plan. Seventy-three articles related to child obesity prevention and control were identified. Most focused on parental behavior change rather than environmental change, and only 3 in 10 articles referred to the social context in which parental behavior change takes place. Child obesity-focused articles were not given high prominence; only one in four articles in the entire sample referred to child obesity as a growing problem or epidemic. Key differences between genres reflect culturally important Latino themes, including family focus and changing health beliefs around child weight status. Given mass media's potential influence on parenting practices and public perceptions, nutrition communication professionals and registered dietitians need to work to reframe media coverage of childhood obesity as an environmental problem that requires broad-based policy solutions. Spanish-speaking media can be an ally in helping Latina women change cultural health beliefs around child weight status. |
23260729 | Positive attitudes toward organic, local, and sustainable foods are associated with higher dietary quality among young adults. | Scant evidence is available on the relationship between preferences for organic, local, sustainable, and nonprocessed foods (ie, alternative food production practices) and dietary quality. This cross-sectional study examined the characteristics and dietary behaviors (eg, consumption of fruits, vegetables, fast food) of young adults who reported placing low, moderate, or high importance on alternative food production practices. A diverse sample of 1,201 students at a 2-year community college and a 4-year public university in the Twin Cities, MN, completed the Student Health and Wellness Study survey in spring 2010. χ(2) tests examined differences in attitudes across demographic characteristics. Linear regression adjusted dietary intake across attitudes. About half (49%) of young adults placed moderate to high importance on alternative production practices, and few demographic differences across attitudes were found. Young adults who placed high importance on alternative production practices consumed 1.3 more servings of fruits and vegetables (P<0.001), more dietary fiber (P<0.001), fewer added sugars (P<0.001), fewer sugar-sweetened beverages (P=0.001), and less fat (P=0.025) than those who placed low importance on these practices. Young adults who placed high importance on alternative food production practices also consumed breakfast approximately 1 more day per week and fast food half as often as those who placed low importance on these practices (P<0.001). Study findings suggest that nutrition messaging around social and environmental implications of food production practices may be well received by this age group. Experimental studies are needed to investigate whether attitudes toward alternative production practices can be manipulated to improve dietary quality. |
23260728 | Characteristics associated with consumption of sports and energy drinks among US adults: National Health Interview Survey, 2010. | Sales of sports and energy drinks have increased dramatically, but there is limited information on regular consumers of sports and energy drinks. Characteristics associated with sports and energy drink intake were examined among a sample representing the civilian noninstitutionalized US adult population. The 2010 National Health Interview Survey data for 25,492 adults (18 years of age or older; 48% males) were used. Nationwide, 31.3% of adults were sports and energy drink consumers during the past 7 days, with 21.5% consuming sports and energy drinks one or more times per week and 11.5% consuming sports and energy drinks three or more times per week. Based on multivariable logistic regression, younger adults, males, non-Hispanic blacks and Hispanics, not-married individuals, adults with higher family income, those who lived in the South or West, adults who engaged in leisure-time physical activity, current smokers, and individuals whose satisfaction with their social activities/relationships was excellent had significantly higher odds for drinking sports and energy drinks one or more times per week. In this model, the factor most strongly associated with weekly sports and energy drink consumption was age (odds ratio [OR]=10.70 for 18- to 24-year-olds, OR=6.40 for 25- to 39-year-olds, OR=3.17 for 40- to 59-year-olds vs 60 years or older). Lower odds for consuming sports and energy drinks one or more times per week were associated with other/multiracial (OR=0.80 vs non-Hispanic white) and obesity (OR=0.87 vs underweight/normal weight). Separate modeling of the association between other beverage intake and sports and energy drink intake showed that higher intake of regular soda, sweetened coffee/tea drinks, fruit drinks, milk, 100% fruit juice, and alcohol were significantly associated with greater odds for drinking sports and energy drinks one or more times per week. These findings can help medical care providers and public health officials identify adults most in need of encouragement to reduce sports and energy drink intake and increase healthier beverage intake. |
23260727 | Regular-soda intake independent of weight status is associated with asthma among US high school students. | Limited research shows an inconclusive association between soda intake and asthma, potentially attributable to certain preservatives in sodas. This cross-sectional study examined the association between regular (nondiet)-soda intake and current asthma among a nationally representative sample of high school students. Analysis was based on the 2009 national Youth Risk Behavior Survey and included 15,960 students (grades 9 through 12) with data for both regular-soda intake and current asthma status. The outcome measure was current asthma (ie, told by doctor/nurse that they had asthma and still have asthma). The main exposure variable was regular-soda intake (ie, drank a can/bottle/glass of soda during the 7 days before the survey). Multivariable logistic regression was used to estimate the adjusted odds ratios for regular-soda intake with current asthma after controlling for age, sex, race/ethnicity, weight status, and current cigarette use. Overall, 10.8% of students had current asthma. In addition, 9.7% of students who did not drink regular soda had current asthma, and 14.7% of students who drank regular soda three or more times per day had current asthma. Compared with those who did not drink regular soda, odds of having current asthma were higher among students who drank regular soda two times per day (adjusted odds ratio=1.28; 95% CI 1.02 to 1.62) and three or more times per day (adjusted odds ratio=1.64; 95% CI 1.25 to 2.16). The association between high regular-soda intake and current asthma suggests efforts to reduce regular-soda intake among youth might have benefits beyond improving diet quality. However, this association needs additional research, such as a longitudinal examination. |
23260726 | Childhood overweight/obesity and asthma: is there a link? A systematic review of recent epidemiologic evidence. | Asthma and overweight/obesity prevalence are both increasing worldwide. Overweight/obesity has been suggested as a risk factor for developing asthma. The aim of this review is to present and evaluate recent publications that help answer the question: "Is increased body weight (at least overweight status) related to asthma in children?" A systematic review of epidemiologic literature was carried out using the MEDLINE database. Epidemiologic studies on young human subjects (ie, infants, children, and adolescents), published in English during the period 2006-2011 were included. A comprehensive literature search yielded 434 studies for further consideration. Forty-eight studies fulfilled the review's eligibility criteria. Two researchers applied the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies on all identified studies. Current evidence supports a weak yet significant association between high body weight and asthma. New information indicates that central obesity in children increases asthma risk. Also, the link between high body weight and asthma may be stronger in nonallergic asthma. There are mixed results about the importance of sex. Although the nature of the association between overweight/obese status and asthma remains unclear, prospective studies point that high body weight precedes asthma symptoms. These data add weight to the importance of preventing and treating a high body weight against asthma outcomes. Available research in children has not studied adequately the influence of weight change (either gain or loss) on asthma symptoms, an area of clinical importance. Beyond energy control, the role of diet as a possible inflammatory stimulus warrants further investigation. Limited data seem to favor the promotion of breastfeeding in attenuating the overweight/obesity-asthma relationship. Finally, future research should include weight intervention studies assessing various measures of body fat in relation to well-defined asthma outcomes. |
23260725 | A qualitative study of diverse experts' views about barriers and strategies to improve the diets and health of Supplemental Nutrition Assistance Program (SNAP) beneficiaries. | The Supplemental Nutrition Assistance Program (SNAP), the largest federal food assistance program, currently serves 44.7 million Americans with a budget of $75 billion in 2011. This study engaged leading experts for in-depth, semi-structured interviews to explore their opinions concerning the existing challenges and barriers to eating nutritiously in SNAP. Experts also proposed strategies for improving nutritional status among SNAP recipients. Twenty-seven individuals were interviewed from advocacy, government, industry, and research organizations. Interviews were recorded, transcribed, coded, and analyzed for thematic content. The high cost of nutrient-rich foods, inadequate SNAP benefits, limited access to purchasing healthy foods, and environmental factors associated with poverty were identified as barriers that influence nutrition among low-income households in the United States. Six themes emerged among respondents from diverse sectors about how to address these challenges, including providing SNAP participants with incentives to purchase nutrient-rich food consistent with the 2010 Dietary Guidelines for Americans, restricting the purchase of nutrient-poor foods and beverages with program benefits, modifying the frequency of SNAP benefit distribution, enhancing nutrition education, improving the SNAP retailer environment, and increasing state and federal level coordination and consistency of program implementation. Given the recent dramatic increase in SNAP enrollment, policymakers must address existing barriers as well as consider new strategies to improve nutrition policies in SNAP so that the program can continue to address food insecurity needs as well as provide a healthful diet for SNAP beneficiaries. |
23260724 | Written messages improve edible food waste behaviors in a university dining facility. | Sustainability and going green have become popular trends among foodservice organizations. Despite this interest, foodservice operations still produce large amounts of edible food waste and contribute significantly to waste management problems. The purpose of this operational study was to determine how to introduce food waste behavior change into a dining facility using a simple message-type intervention that requires little sustained administrative support and can provide optimum effect. The population for this study was 540 university students living in residence halls and participating in a meal plan. This study assessed whether simple prompt-type message interventions had an influence or if the addition of more personally relevant feedback-based data elicited greater change in student beliefs and food waste behaviors. A written questionnaire and individual student tray waste tracking were used to gather data. Simple print-format messages were evaluated, allowing the effect of an affordable message campaign to be determined. Students had a higher-than-neutral level of belief, but did not indicate a strong conviction toward environmental sustainability or food waste. The edible food items disposed of on 19,046 trays in this all-you-care-to-eat university dining operation were evaluated. On average, more than 57 g edible food was disposed of per tray, accumulating to >1.5 tons of food waste during the 6-week study. The simple to-the-point prompt-type message stimulated a 15% reduction in food waste. The addition of a more personalized feedback-based message did not stimulate an additional change beyond that of the prompt message. These findings indicate that simply making university students aware of the topic of food waste may be useful in improving their behaviors and the sustainability of the foodservice facility. |
23260722 | Trends in dietary intake among US 2- to 6-year-old children, 1989-2008. | Between 1989 and 2008, obesity increased markedly in children of all ages. We examined changes in the diets of children ages 2 to 6 years in the United States between 1989 and 2008. Our study provides new insight into diet changes that might have contributed to the sharp rise in obesity during this period. Our aim was to describe changes in diet among 2- to 6-year-old children from 1989 to 2008 related to sharp rises in obesity during this period. This analysis included 10,647 children ages 2 to 6 years from the following five nationally representative surveys of dietary intake in the United States: Continuing Survey of Food Intake in Individuals 1989-1991 and 1994-1998 and the What We Eat In America, National Health and Nutrition Examination Surveys 2003-2004, 2005-2006, and 2007-2008. Diet data were categorized into groupings using the University of North Carolina-Chapel Hill approach. Analyses were carried out using a single 24-hour dietary recall with appropriate survey weighting. T tests were used to compare means across survey years, with P<0.05 considered significant. During the 20-year period, there were increases in per capita intake of savory snacks (+51 kcal; P<0.01), pizza/calzones (+32 kcal; P<0.01), sweet snacks and candy (+25 kcal; P<0.01), mixed Mexican dishes (+22 kcal; P<0.01), and fruit juice (+18 kcal; P<0.01), and total daily energy intake increased by 109 kcal (from 1,475 to 1,584 kcal) (P<0.05). Fruit intake increased marginally (+24 kcal; P<0.01). Six of the 10 greatest absolute changes in per capita intake between sequential survey years occurred between Continuing Survey of Food Intake in Individuals 1994-1998 and National Health and Nutrition Examination Surveys 2003-2004 (P<0.05). Foods high in added sugars and solid fats, such as savory snacks, pizza/calzones, mixed Mexican dishes, sweet snacks and candy, and fruit juice, predominated the top changes in per capita consumption between 1989 and 2008. |
23260717 | Human gastroenteritis outbreak associated with Escherichia albertii, Japan. | Although Escherichia albertii is an emerging intestinal pathogen, it has been associated only with sporadic human infections. In this study, we determined that a human gastroenteritis outbreak at a restaurant in Japan had E. albertii as the major causative agent. |
23260716 | On statistical inference in time series analysis of the evolution of road safety. | Data collected for building a road safety observatory usually include observations made sequentially through time. Examples of such data, called time series data, include annual (or monthly) number of road traffic accidents, traffic fatalities or vehicle kilometers driven in a country, as well as the corresponding values of safety performance indicators (e.g., data on speeding, seat belt use, alcohol use, etc.). Some commonly used statistical techniques imply assumptions that are often violated by the special properties of time series data, namely serial dependency among disturbances associated with the observations. The first objective of this paper is to demonstrate the impact of such violations to the applicability of standard methods of statistical inference, which leads to an under or overestimation of the standard error and consequently may produce erroneous inferences. Moreover, having established the adverse consequences of ignoring serial dependency issues, the paper aims to describe rigorous statistical techniques used to overcome them. In particular, appropriate time series analysis techniques of varying complexity are employed to describe the development over time, relating the accident-occurrences to explanatory factors such as exposure measures or safety performance indicators, and forecasting the development into the near future. Traditional regression models (whether they are linear, generalized linear or nonlinear) are shown not to naturally capture the inherent dependencies in time series data. Dedicated time series analysis techniques, such as the ARMA-type and DRAG approaches are discussed next, followed by structural time series models, which are a subclass of state space methods. The paper concludes with general recommendations and practice guidelines for the use of time series models in road safety research. |
23260712 | VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients. | Cardiac allograft vasculopathy (CAV), the major cause of late allograft loss after cardiac transplantation, results from donor-directed cellular and humoral alloimmune responses. Graft vascular endothelial cells (EC) are primary targets of these destructive responses, suggesting that factors associated with endothelial injury and repair could serve as biomarkers of CAV. Using a protein profiler array platform, we measured the levels of 55 angiogenesis-related proteins in sera from 33 adult heart transplant recipients, including 17 with angiographically documented CAV and 16 age- and gender-matched controls without CAV. All patients were >2 years after heart transplant. The study population was 75% male with a mean age of 62 ± 11 years. On average, patients were 12 ± 5 years after heart transplantation. We found that vascular endothelial growth factor (VEGF)-C, VEGF-A, angiopoietin-2, artemin, urokinase-type plasminogen activator and vasohibin were strongly associated with established CAV (all p < 0.01). Multivariable modeling identified VEGF-C, VEGF-A and platelet factor-4 (PF-4) as significant independent biomarkers of CAV. Furthermore, receiver-operating characteristic curve analysis demonstrated that the combination of all 3 molecules provided outstanding performance for the diagnosis of CAV (area under the curve [AUC] = 0.98; p < 0.001). Serum levels of VEGF-C, VEGF-A and PF-4 demonstrate strong associations with established CAV and, together with related angiogenesis factors, may serve as a reliable, non-invasive diagnostic test for CAV in cardiac transplant recipients. |
23260713 | Recurrent orthostatic syncope due to left atrial and left ventricular collapse after a continuous-flow left ventricular assist device implantation. | Left ventricular assist devices (LVADs) have become an established treatment for patients with advanced heart failure as a bridge to transplantation or for permanent support as an alternative to heart transplantation. Continuous-flow LVADs have been shown to improve outcomes, including survival, and reduce device failure compared with pulsatile devices. Although LVADs have been shown to be a good option for patients with end-stage heart failure, unanticipated complications may occur. We describe dynamic left atrial and left ventricular chamber collapse related to postural changes in a patient with a recent continuous-flow LVAD implantation. |
23260711 | Pre-clinical evaluation of the infant Jarvik 2000 heart in a neonate piglet model. | The infant Jarvik 2000 heart is a very small, hermetically sealed, intracorporeal, axial-flow ventricular assist device (VAD) designed for circulatory support in neonates and infants. The anatomic fit, short-term biocompatibility and hemodynamic performance of the device were evaluated in a neonate piglet model. The infant Jarvik 2000 heart with two different blade profiles (low- or high-flow blade design) was tested in 6 piglets (8.8 ± 0.9 kg). Using a median sternotomy, the pump was placed in the left ventricle through the apex without cardiopulmonary bypass. An outflow graft was anastomosed to the ascending aorta. Hemodynamics and biocompatibility were studied for 6 hours. All 6 pumps were implanted without complication. Optimal anatomic positioning was found with the pump body inserted 2.4 cm into the left ventricle. Hemodynamics demonstrated stability throughout the 6-hour duration. The pump flow increased from 0.27 to 0.95 liter/min at increasing speeds from 18 to 31 krpm for the low-flow blade design, whereas the pump flow increased from 0.54 liter/min to 1.12 liters/min at increasing speeds from 16 krpm to 31 krpm for the high-flow blade design. At higher speeds, >80% of flow could be supplied by the device. Blood chemistry and final pathology demonstrated no acute organ injury or thrombosis for either blade design. The infant Jarvik 2000 heart is anatomically and biologically compatible with an short-term neonate piglet model. This in vivo study demonstrates the future feasibility of this device for clinical use. |
23260710 | Clinical outcome of mechanical circulatory support for refractory cardiogenic shock in the current era. | Mortality for refractory cardiogenic shock (RCS) remains high. However, with improving mechanical circulatory support device (MCSD) technology, the treatment options for RCS patients are expanding. We report on a recent 5-year single-center experience with MCSD for treatment of RCS. This study was a retrospective review of adult patients who required an MCSD due to RCS in the past 5 years. We excluded those patients with post-cardiotomy shock and post-transplant cardiac graft dysfunction. In the setting of RCS, a short-term ventricular assist device (VAD) was inserted as a bridge-to-decision device. Veno-arterial extracorporeal membrane oxygenation (VA ECMO) was chosen in cases of unknown neurologic status, complete hemodynamic collapse or severe coagulopathy. From January 2007 through January 2012, 90 patients received an MCSD for RCS, 21 (23%) of whom had active cardiopulmonary resuscitation (CPR). The etiology of RCS included acute myocardial infarction in 49% and acute decompensated heart failure in 27%. Mean age was 53±14 years, 71% were male, and 60% had an intra-aortic balloon pump. The initial approach utilized was short-term VAD in 49% and VA ECMO in 51%. Median length of support was 8 days (IQR 4 to 18 days). Exchange to implantable VAD was performed in 26% of patients. Other destinations included myocardial recovery in 18% and heart transplantation in 11%. Survival to hospital discharge was 49%. Multivariate analysis showed ongoing CPR to be an independent risk factor for mortality (OR = 5.79, 95% CI 1.285 to 26.08, p = 0.022). In the current era, roughly half of the patients who need an MCSD for RCS survive, and roughly half of these survivors require an implantable VAD. Ongoing CPR is predictive of in-hospital mortality. |
23260709 | Utility of C4d immunostaining in the first year after pediatric and young adult heart transplantation. | C4d assessment of endomyocardial biopsies (EMBs) after heart transplantation (HTx) has been widely adopted to aid in the diagnosis of antibody-mediated rejection (AMR), yet it remains unclear whether or not to assess all patients routinely and with what frequency/duration. In this study we sought to evaluate the utility of routine C4d immunostaining in the first year after pediatric and young adult HTx. We reviewed pre-transplant alloantibody and clinical data, including serial EMB reports, on all 51 patients who received HTx at our center since we instituted routine C4d staining of all first-year EMBs. C4d was considered positive if diffuse capillary staining (≥ 2(+)) was present. Rare/focal capillary staining or absence of staining was considered negative. Twenty-six of 406 first-year EMBs (6%) were C4d(+) in 6 (12%) patients. Sixty-five percent of all C4d(+) EMBs occurred by 30 days post-transplant. Five of 6 patients had pre-transplant donor-specific antibody (DSA) ≥ 4,000 MFI. The sixth patient had neither pre-transplant anti-HLA antibodies nor a positive donor-specific cytotoxicity crossmatch (DSXM), but there was clinical concern for AMR. Among the entire cohort, 5 of 10 patients with pre-transplant DSA ≥ 4,000 MFI and/or a positive DSXM were C4d(+) compared with only 1 of 41 without (50% vs 2%; p = 0.001). In the first year after HTx, C4d(+) occurred early and only in children and young adults with pre-transplant DSA or with clinical suspicion of AMR. Although our data suggest that assessment limited to the first 90 days post-transplant in patients with pre-transplant DSA ≥ 4,000 MFI may be appropriate in the absence of clinical concern for AMR, further research is needed to determine the optimum strategy for post-transplant surveillance. |
23260708 | An unexpectedly high prevalence of undiagnosed diabetes in patients awaiting lung transplantation. | Diabetes mellitus (DM) is a common complication after lung transplantation but its prevalence prior to transplantation has not been determined. We sought to determine the prevalence of and risk factors for DM in adults awaiting lung transplantation and to determine whether pre-transplant DM could be diagnosed by hemoglobin A1c (HbA1c) alone. All patients wait-listed for lung transplantation over a 2-year period had HbA1c measured. Those not known to have DM also underwent an oral glucose tolerance test (OGTT) with insulin levels. Of 190 patients listed for lung transplantation, 30 (16%) had been diagnosed previously with DM. Twelve patients received transplants and 1 came off the waiting list before having an OGTT. The remaining patients underwent OGTT: 14 were newly diagnosed with DM and 29 with pre-diabetes. One patient vomited during the test and was excluded from analyses. Thus, 41% of all screened waiting list patients had DM (known or newly diagnosed) or pre-diabetes. Neither age, BMI, prednisolone dose nor family history correlated with dysglycemia. Patients with newly diagnosed DM and pre-diabetes were more insulin-resistant than those with normoglycemia. HbA(1c) correlated poorly with OGTT. Patients awaiting lung transplantation have unexpectedly high rates of DM and pre-diabetes despite close medical follow-up. Screening for DM with an OGTT will allow early intervention, which may improve outcomes after transplantation. |
23260707 | Clinical implications of chronic hepatitis E virus infection in heart transplant recipients. | Recent reports have shown that hepatitis E virus (HEV) infection can become chronic in solid-organ transplant recipients, but few studies have systematically investigated the clinical consequences of this chronic HEV infection in solid-organ transplant (SOT) recipients. We have undertaken an in-depth study of 6 chronic HEV-infected heart transplant recipients to gain further insight into the clinical, biochemical and virologic presentation of this disorder. In 6 patients (2.3%) chronic HEV infection, genotype 3, was identified. Immunosuppression in these patients was tacrolimus-based, combined with either everolimus or prednisolone and/or mycophenolate mofetil. Median follow-up after case detection was 26 months (range 21 to 40 months). All chronic HEV cases had elevated liver enzyme values. IgM antibodies at presentation were positive in 2 of 6 (33%) patients. Liver histology in 4 of 6 (67%) patients showed advanced fibrosis within 2 years after infection. One patient spontaneously cleared the HEV infection: 1 after dose reduction of immunosuppressive therapy and 3 during ribavirin therapy. One patient has yet to clear the virus and remains on ribavirin therapy. Chronic HEV infection in heart transplant (HTx) recipients may lead to rapid fibrosis of the liver. We advise additional HEV RNA screening in solid-organ transplant recipients with elevated liver enzymes, because antibody production is often delayed, as demonstrated in these patients. Dose reduction of immunosuppressive therapy should be the first intervention strategy to achieve viral clearance in chronic HEV-infected immunocompromised patients. Ribavirin treatment should be considered in cases of chronic HEV. |
23260706 | Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cystic fibrosis after lung transplantation. | Lung transplantation is limited by chronic lung allograft dysfunction. Acute cellular rejection (ACR) is a risk factor for allograft dysfunction; however, the role of antibody-mediated rejection (AMR) is not well characterized. This was a retrospective review from 2007 to 2011 of lung transplant recipients with human leukocyte antigen (HLA) antibody testing using Luminex (Luminex Corp, Austin, TX) single-antigen beads. Statistics included Fisher's exact test for significance. Donor-specific antibodies (DSA) developed in 13 of 44 patients. Of the 13 with DSA, 12 had cystic fibrosis compared with 18 of 31 in the non-DSA group (p = 0.035). Of those with DSAs, 23.1% occurred within the first year, and 69.2% occurred between 1 and 3 years. Twelve of 13 DSA patients had anti-HLA DQ specificity compared with 2 of 31 non-DSA patients (p = 0.0007). AMR developed in 10 of the 13 DSA patients compared with 1 of 31 non-DSA patients (p = 0.0001). The DSA group experienced 2.6 episodes/patient of cellular rejection vs 1.7 episodes/patient in the non-DSA group (p = 0.059). Bronchiolitis obliterans syndrome developed in 11 of 13 in the DSA group vs 10 of 31 in the non-DSA group (p = 0.0024). In the DSA group, 11.5% HLAs matched compared with 20.4% in the non-DSA group (p = 0.093). AMR developed in 11 of 22 patients in the non-DSA HLA group compared with 0 of 22 in the group without non-DSA HLA antibodies (p = 0.002). Survival at 1 and 3 years was 92% and 36% in the DSA group, respectively, and 97% and 65% in the non-DSA group. DSAs and non-DSAs occur frequently after lung transplantation. DSAs are prevalent in the cystic fibrosis population and are associated with AMR, bronchiolitis obliterans syndrome, and possibly, ACR. |
23260705 | Left ventricular distensibility does not explain impaired exercise capacity in pediatric heart transplant recipients. | Despite improved ventricular function after heart transplantation, the aerobic capacity, as measured by peak oxygen consumption (VO(2 peak)) of pediatric heart transplant recipients (HTRs), remains 30% to 50% lower than age-matched healthy individuals. Research in adult HTRs suggests that diastolic dysfunction is a major determinant of exercise intolerance; however, it is unknown whether the impaired VO(2 peak) in younger HTRs is due to reduced left ventricular (LV) distensibility. Eight HTRs (mean age, 15 years; mean time post-transplant, 7 years) and 8 matched healthy controls were studied. To evaluate LV distensibility, echocardiographic measurements of ventricular volumes were obtained in 3 positions: supine, head-up tilt, and head-down tilt. Subsequently, participants underwent exercise stress testing to evaluate VO(2 peak). As expected, VO(2 peak) was 26% lower in HTRs (p<0.05). Ventricular volumes in each position were small in HTRs (p = 0.01); however, the percentage change in LV end-diastolic volume indexed (EDVi) to body surface area after the transition from supine to head-up tilt and from head-up tilt to head-down tilt were similar between HTRs (p = 0.956) and controls (p = 0.801). The change in EDVi during the transition from head-up tilt to head-down tilt (LV distensibility) strongly predicted VO(2 peak) in patients (R(2) = 0.614, p = 0.021) and controls (R(2) = 0.510, p = 0.047). Importantly, the slope of this relationship did not differ between HTRs (1.01) and controls (0.977; p = 0.951). LV distensibility does not appear to be a major determinant of exercise intolerance in young HTR. |
23260704 | Bronchiolitis obliterans syndrome, hypogammaglobulinemia, and infectious complications of lung transplantation. | Because infection has been associated with the development of bronchiolitis obliterans syndrome (BOS), we hypothesized that post-transplant hypogammaglobulinemia would be associated with infection and BOS. Cross-sectional levels of serum immunoglobulins were measured on 2 occasions in our transplant cohort and models developed to explain serum immunoglobulin levels and BOS-free survival. A total of 139 patients (median age, 46.6 years) were evaluated at 47 months (range, 15-74 months) after transplant, and 87 were re-evaluated at 72 months (40-107 months). Of this cohort, 44% were immunoglobulin (Ig) G deficient and levels remained stable across the study period, and 27% were IgA deficient and levels fell slightly over time (p = 0.003). Both immunoglobulin classes were lower in patients with a history of invasive fungal infection, whereas IgA levels were lower in patients with a history of community-acquired respiratory viral infection. Low IgG was independently associated with shorter BOS-free survival (hazard ratio, 0.79; 95% confidence interval, 0.71-0.88; p<0.001). Serum immunoglobulin deficiency is common after lung transplantation and is associated with community-acquired respiratory viral infection, invasive fungal infection, and BOS. |
23260703 | Progression pattern of restrictive allograft syndrome after lung transplantation. | Restrictive allograft syndrome (RAS) is a novel form of chronic lung allograft dysfunction after lung transplantation. RAS is characterized by restrictive physiology and peripheral lung fibrosis. The purpose of the study is to analyze progression patterns of RAS. Clinical information, pulmonary function test results and radiographic findings were reviewed for 25 RAS patients who received bilateral lung or heart-lung transplantation between January 2004 and December 2009. Average time from transplantation to RAS onset was 647 ± 544 (mean ± SD) days; RAS onset to end of observation (death or re-transplantation) was 490 ± 417 days. RAS patients had 1 to 4 episodes of acute exacerbation (2.48 ± 0.82 episodes/patient) that accompanied acute respiratory deterioration or distress, a sudden drop in pulmonary function, evidence of diffuse alveolar damage (DAD) on biopsies, and patchy or diffuse ground-glass opacities (GGO) with occasional consolidation on computed tomography scan. Patients were most frequently managed by high-dose steroid in combination with empirical antibiotics, with uncertain efficacy. Acute exacerbation was followed by an interval during which resolution of GGO and progression of consolidation, interstitial reticular shadows and traction bronchiectasis were frequently observed. The interval between episodes of acute exacerbation was 238 ± 165 days. In 21 patients, the last episode of acute exacerbation led to death or urgent retransplantation. RAS shows a "stair-step" pattern of progression. Acute lung injury represented by DAD and GGO is followed by an interval period during which graft fibrosis often progresses. |
23260699 | Axial and centrifugal continuous-flow rotary pumps: a translation from pump mechanics to clinical practice. | The recent success of continuous-flow circulatory support devices has led to the growing acceptance of these devices as a viable therapeutic option for end-stage heart failure patients who are not responsive to current pharmacologic and electrophysiologic therapies. This article defines and clarifies the major classification of these pumps as axial or centrifugal continuous-flow devices by discussing the difference in their inherent mechanics and describing how these features translate clinically to pump selection and patient management issues. Axial vs centrifugal pump and bearing design, theory of operation, hydrodynamic performance, and current vs flow relationships are discussed. A review of axial vs centrifugal physiology, pre-load and after-load sensitivity, flow pulsatility, and issues related to automatic physiologic control and suction prevention algorithms is offered. Reliability and biocompatibility of the two types of pumps are reviewed from the perspectives of mechanical wear, implant life, hemolysis, and pump deposition. Finally, a glimpse into the future of continuous-flow technologies is presented. |
23260683 | Highly sensitive detection of human cardiac myoglobin using a reverse sandwich immunoassay with a gold nanoparticle-enhanced surface plasmon resonance biosensor. | A highly sensitive reverse sandwich immunoassay for the detection of human cardiac myoglobin (cMb) in serum was designed utilizing a gold nanoparticle (AuNP)-enhanced surface plasmon resonance (SPR) biosensor. First, a monoclonal anti-cMb antibody (Mab1) was covalently immobilized on the sensor surface. AuNPs were covalently conjugated to the second monoclonal anti-cMb antibody (Mab2) to form an immuno-gold reagent (Mab2-AuNP). The reverse sandwich immunoassay consists of two steps: (1) mixing the serum sample with Mab2-AuNP and incubation for the formation of cMb/Mab2-AuNP complexes and (2) sample injection over the sensor surface and evaluation of the Mab1/cMb/Mab2-AuNP complex formation, with the subsequent calculation of the cMb concentration in the serum. The biosensor signal was amplified approximately 30-fold compared with the direct reaction of cMb with Mab1 on the sensor surface. The limit of detection of cMb in a human blood serum sample was found to be as low as 10 pM (approx. 0.18 ng mL(-1)), and the inter-assay coefficient of variation was less than 3%. Thus, the developed SPR-based reverse sandwich immunoassay has a sensitivity that is sufficient to measure cMb across a wide range of normal and pathological concentrations, allowing an adequate estimation of the disease severity and the monitoring of treatment. |
23260682 | Comparison of an antibody and its recombinant derivative for the detection of the small molecule explosive 2,4,6-trinitrotoluene. | Antibodies are commonly used as recognition elements in immunoassays because of their high specificity and affinity, and have seen extensive use in competitive assays for the detection of small molecules. However, these complex molecules require production either in animals or by mammalian cell cultures, and are not easily tailored through genetic manipulation. Single chain antibodies (scFv), recombinantly expressed molecules consisting of only the antibody's binding region joined via a linking peptide, can provide an alternative to intact antibodies. We describe the characterization of a new monoclonal antibody (mAb), 2G5B5, able to detect the small molecule explosive 2,4,6-trinitrotoluene (TNT) and the scFv derived from its variable regions. The mAb and scFv were tested by surface plasmon resonance to determine their affinity for an immobilized TNT surrogate; dissociation constants were determined to be 1.5×10(-13) M and 4.8×10(-10) M respectively. Circular dichroism was used to determine their melting temperatures. The mAb is more stable melting at ∼75°C while the scFv melts at ∼65°C. The recognition elements were incorporated into a competitive assay format using a bead-based multiplexing platform to examine their sensitivity and specificity. The scFv was able to detect TNT ∼10-fold more sensitively than the mAb in this assay format, allowing detection of TNT concentrations down to at least 1 μg L(-1). The 2G5B gave similar detection limits to a commercial anti-TNT mAb, but was less specific, recognizing 1,3,5-trinitrobenzene (TNB) equally well as TNT. |
23260681 | A competitive displacement assay with quantum dots as fluorescence resonance energy transfer donors. | The unique optoelectronic properties of semiconductor quantum dots (QDs) make them well-suited as fluorescent bioprobes for use in various biological applications. Modification of CdSe/ZnS QDs with biologically relevant molecules provides for multipotent probes that can be used for cellular labeling, bioassays, and localized optical interrogation by means of fluorescence resonance energy transfer (FRET). Herein, we demonstrate the use of red-emitting streptavidin-coated QDs (QD(605)) as donors in FRET to introduce a competitive displacement-based assay for the detection of oligonucleotides. Various QD-DNA bioconjugates featuring 25-mer probe sequences diagnostic of Hsp23 were prepared. The single-stranded oligonucleotide probes were hybridized to dye-labeled (Alexa Fluor 647) reporter sequences, which were provided for a FRET-sensitized emission signal due to proximity of the QD and dye. The dye-labeled sequence was designed to be partially complementary and include base-pair mismatches to facilitate displacement by a more energetically favorable, fully complementary recognition motif embedded within a 98-mer displacer sequence. Overall, this study demonstrates proof-of-concept at the nM level for competitive displacement hybridization assays in vitro by reduction of fluorescence intensity that directly correlates to the presence of oligonucleotides of interest. This work demonstrates an analytical method that could potentially be implemented for monitoring of intracellular gene expression in the future. |
23260680 | Luminescence recognition of different organophosphorus pesticides by the luminescent Eu(III)-pyridine-2,6-dicarboxylic acid probe. | Luminescence quenching of a novel long lived Eu(III)-pyridine-2,6-dicarboxylic acid probe of 1:2 stoichiometric ratio has been studied in 0.10 volume fraction ethanol-water mixture at pH 7.5 (HEPES buffer) in the presence of the organophosphorus pesticides chlorfenvinphos (P1), malathion (P2), azinphos (P3), and paraxon ethyl (P4). The luminescence intensity of Eu(III)-(PDCA)(2) probe decreases as the concentration of the pesticide increases. It was observed that the quenching due to P3 and P4 proceeds via both diffusional and static quenching processes. Direct methods for the determination of the pesticides under investigation have been developed using the luminescence quenching of Eu(III)-pyridine-2,6-dicarboxylic acid probe in solution. The linear range for determination of the selected pesticides is 1.0-35.0 μM. The detection limits were 0.24-0.55 μM for P3, P4, and P1 and 2.5 μM for P2, respectively. The binding constants (K), and thermodynamic parameters of the OPs with Eu(III)-(PDCA)(2) were evaluated. Positive and negative values of entropy (ΔS) and enthalpy (ΔH) changes for Eu(III)-(PDCA)(2)-P1 ternary complex were calculated. As the waters in this study do not contain the above mentioned OPs over the limit detectable by the method, a recovery study was carried out after the addition of the adequate amounts of the organophosphorus pesticides under investigation. |
23260679 | Label-free electrochemical monitoring of vasopressin in aptamer-based microfluidic biosensors. | Vasopressin is an indicating biomarker for blood pressure in the human body and low vasopressin levels can be indicative of late-phase hemorrhagic shock or other traumatic injuries. In this paper we have developed an aptamer-based label-free microfluidic biosensor for the electrochemical detection of vasopressin. The detection area consists of aptamers immobilized on carbon nanotubes which specifically capture the vasopressin molecules in solution resulting in changes in conductivity across the sensor. We report a limit of detection of 43 pM in standard solutions and demonstrate high detection specificity toward vasopressin when different interferents are present. The miniaturized microfluidic biosensor offers continuous monitoring of different vasopressin levels with good potential for portability. Ultimately such a system could serve as a point-of-care diagnostics tool for patients with excessive bleeding when standard medical infrastructure is not available. |
23260678 | A reliable and simple method for the assay of neuroendocrine tumor markers in human urine by solid-phase microextraction-gas chromatography-triple quadrupole mass spectrometry. | Homovanillic acid (HVA), vanylmandelic acid (VMA), and 5-hydroxyindoleacetic acid (5-HIAA) are the metabolites of some catecholamines such as epinephrine, nor-epinephrine, dopamine and serotonin and their quantification is used in the diagnosis and management of patients with neurocrine tumors. A novel approach in the assay of these biomarkers in human urine samples by solid phase microextraction (SPME) combined with gas chromatography-triple quadrupole mass spectrometry (GC-QqQ-MS) is presented. A preliminary derivatization with ethyl chloroformate/ethanol was used and the corresponding derivatives were then extracted by SPME in immersion mode. The performance of five SPME fibers and three chloroformates were evaluated in univariate mode and the best results were obtained using the polyacrylate fiber and ethyl chloroformate. The variables affecting the efficiency of SPME analysis were optimized by the multivariate approach of "Experimental design" and, in particular, a central composite design (CCD) was applied. The optimum working conditions in terms of response values were achieved by performing analysis at room temperature with addition of NaCl (9.5%) and with an extraction time of 25.8 min. Identification and quantification of analytes were carried out by using a gas chromatography-triple quadrupole mass spectrometry (GC-QqQ MS) system in multiple reaction monitoring (MRM) acquisition. An evaluation of all analytical parameters shows that the proposed method provides satisfactory results. Very good linearities were, in fact, achieved in the tested calibration ranges with correlation coefficient values >0.99 for all the analytes and accuracies and RSDs calculated for between-run and tested at concentrations of 1, 10, and 80 mg L(-1) were ranging from 91.3% to 106.6%, and from 0.5 to 8.9%, respectively. Moreover, the LOD values obtained can be considered very satisfactory (1.3, 0.046 and 24.3 μg L(-1) for HVA, VMA and 5-HIAA, respectively). The developed protocol represents, therefore, a simple, rapid and selective tool for assaying these acidic biomarkers in urine samples for neuroendocrine cancer diagnosis. |
23260677 | An aptamer-based biosensing platform for highly sensitive detection of platelet-derived growth factor via enzyme-mediated direct electrochemistry. | In this work, a new label-free electrochemical aptamer-based sensor (aptasensor) was constructed for detection of platelet-derived growth factor (PDGF) based on the direct electrochemistry of glucose oxidase (GOD). For this proposed aptasensor, poly(diallyldimethylammonium chloride) (PDDA)-protected graphene-gold nanoparticles (P-Gra-GNPs) composite was firstly coated on electrode surface to form the interface with biocompatibility and huge surface area for the adsorption of GOD layer. Subsequently, gold nanoclusters (GNCs) were deposited on the surface of GOD to capture PDGF binding aptamer (PBA). Finally, GOD as a blocking reagent was employed to block the remaining active sites of the GNCs and avoid the nonspecific adsorption. With the direct electron transfer of double layer GOD membranes, the aptasensor showed excellent electrochemical response and the peak current decreased linearly with increasing logarithm of PDGF concentration from 0.005 nM to 60 nM with a relatively low limit of detection of 1.7 pM. The proposed aptasensor exhibited high specificity, good reproducibility and long-term stability, which provided a new promising technique for aptamer-based protein detection. |
23260676 | Apoferritin protein nanoparticles dually labeled with aptamer and horseradish peroxidase as a sensing probe for thrombin detection. | A novel and ultrasensitive sandwich-type electrochemical aptasensor has been developed for the detection of thrombin, based on dual signal-amplification using HRP and apoferritin. Core/shell Fe(3)O(4)/Au magnetic nanoparticles (AuMNPs) loading aptamer1 (Apt1) was used as recognition elements, and apoferritin dually labeled with Aptamer2 (Apt2) and HRP was used as a detection probe. Sandwich-type complex, Apt1/thrombin/Apt2-apoferritin NPs-HRP was formed by the affinity reactions between AuMNPs-Apt1, thrombin, and Apt2-apoferritin-HRP. The complex was anchored on a screen-printed carbon electrode (SPCE). Differential pulse voltammetry (DPV) was used to monitor the electrode response. The proposed aptasensor yielded a linear current response to thrombin concentrations over a broad range of 0.5-100 pM with a detection limit of 0.07 pM (S/N=3). The detection signal was amplified by using apoferritin and HRP. This nanoparticle-based aptasensor offers a new method for rapid, sensitive, selective, and inexpensive quantification of thrombin, and offers a promising potential in protein detection and disease diagnosis. |
23260675 | The influence of R and S configurations of a series of amphetamine derivatives on quantitative structure-activity relationship models. | Chiral molecules need special attention in drug design. In this sense, the R and S configurations of a series of thirty-four amphetamines were evaluated by quantitative structure-activity relationship (QSAR). This class of compounds has antidepressant, anti-Parkinson and anti-Alzheimer effects against the enzyme monoamine oxidase A (MAO A). A set of thirty-eight descriptors, including electronic, steric and hydrophobic ones, were calculated. Variable selection was performed through the correlation coefficients followed by the ordered predictor selection (OPS) algorithm. Six descriptors (CHELPG atomic charges C3, C4 and C5, electrophilicity, molecular surface area and logP) were selected for both configurations and a satisfactory model was obtained by PLS regression with three latent variables with R(2)=0.73 and Q(2)=0.60, with external predictability Q(2)=0.68, and R(2)=0.76 and Q(2)=0.67 with external predictability Q(2)=0.50, for R and S configurations, respectively. To confirm the robustness of each model, leave-N-out cross validation (LNO) was carried out and the y-randomization test was used to check if these models present chance correlation. Moreover, both automated or a manual molecular docking indicate that the reaction of ligands with the enzyme occurs via pi-pi stacking interaction with Tyr407, inclined face-to-face interaction with Tyr444, while aromatic hydrogen-hydrogen interactions with Tyr197 are preferable for R instead of S configurations. |
23260674 | Assessment of applicability domain for multivariate counter-propagation artificial neural network predictive models by minimum euclidean distance space analysis: a case study. | Alongside the validation, the concept of applicability domain (AD) is probably one of the most important aspects which determine the quality as well as reliability of the established quantitative structure-activity relationship (QSAR) models. To date, a variety of approaches for AD estimation have been devised which can be applied to particular type of QSAR models and their practical utilization is extensively elaborated in the literature. The present study introduces a novel, simple, and effective distance-based method for estimation of the AD in case of developed and validated predictive counter-propagation artificial neural network (CP ANN) models through a proficient exploitation of the euclidean distance (ED) metric in the structure-representation vector space. The performance of the method was evaluated and explained in a case study by using a pre-built and validated CP ANN model for prediction of the transport activity of the transmembrane protein bilitranslocase for a diverse set of compounds. The method was tested on two more datasets in order to confirm its performance for evaluation of the applicability domain in CP ANN models. The chemical compounds determined as potential outliers, i.e., outside of the CP ANN model AD, were confirmed in a comparative AD assessment by using the leverage approach. Moreover, the method offers a graphical depiction of the AD for fast and simple determination of the extreme points. |
23260673 | Classification of time-of-flight secondary ion mass spectrometry spectra from complex Cu-Fe sulphides by principal component analysis and artificial neural networks. | Artificial neural network (ANN) and a hybrid principal component analysis-artificial neural network (PCA-ANN) classifiers have been successfully implemented for classification of static time-of-flight secondary ion mass spectrometry (ToF-SIMS) mass spectra collected from complex Cu-Fe sulphides (chalcopyrite, bornite, chalcocite and pyrite) at different flotation conditions. ANNs are very good pattern classifiers because of: their ability to learn and generalise patterns that are not linearly separable; their fault and noise tolerance capability; and high parallelism. In the first approach, fragments from the whole ToF-SIMS spectrum were used as input to the ANN, the model yielded high overall correct classification rates of 100% for feed samples, 88% for conditioned feed samples and 91% for Eh modified samples. In the second approach, the hybrid pattern classifier PCA-ANN was integrated. PCA is a very effective multivariate data analysis tool applied to enhance species features and reduce data dimensionality. Principal component (PC) scores which accounted for 95% of the raw spectral data variance, were used as input to the ANN, the model yielded high overall correct classification rates of 88% for conditioned feed samples and 95% for Eh modified samples. |
23260672 | Characterisation of hydrogen bond perturbations in aqueous systems using aquaphotomics and multivariate curve resolution-alternating least squares. | Aquaphotomics is a new discipline that provides a framework for understanding changes in the structure of water caused by various perturbations, such as variations in temperature or the addition of solutes, using near infrared spectroscopy (NIRS). One of the main purposes of aquaphotomics is to identify water bands as main coordinates of future absorbance patterns to be used as biomarkers. These bands appear as consequence of perturbations in the NIR spectra. Curve resolution techniques may help to resolve and find new water bands or confirm already known bands. The aim of this study is to investigate the application of multivariate curve resolution-alternating least squares (MCR-ALS) to characterise the effects of various perturbations on the NIR spectra of water in terms of hydrogen bonding. For this purpose, the perturbations created by temperature change and the addition of four solutions of different ionic strength and Lewis acidity were studied (NaCl, KCl, MgCl(2) and AlCl(3), with concentrations ranging from 0.2 to 1 mol L(-1) in steps of 0.2 mol L(-1)). Transmission spectra of all salt solutions and pure water were obtained at temperatures ranging from 28 to 45°C. We have found that three distinct components with varying temperature dependence are present in water perturbed by temperature. The salt solutions studied exhibited similar trends with respect to the temperature perturbation, while the peak locations of their MCR-ALS pure components varied according to the ionic strength of the salt used. |
23260668 | Poised RNA polymerase II changes over developmental time and prepares genes for future expression. | Poised RNA polymerase II (Pol II) is predominantly found at developmental control genes and is thought to allow their rapid and synchronous induction in response to extracellular signals. How the recruitment of poised RNA Pol II is regulated during development is not known. By isolating muscle tissue from Drosophila embryos at five stages of differentiation, we show that the recruitment of poised Pol II occurs at many genes de novo and this makes them permissive for future gene expression. A comparison with other tissues shows that these changes are stage specific and not tissue specific. In contrast, Polycomb group repression is tissue specific, and in combination with Pol II (the balanced state) marks genes with highly dynamic expression. This suggests that poised Pol II is temporally regulated and is held in check in a tissue-specific fashion. We compare our data with findings in mammalian embryonic stem cells and discuss a framework for predicting developmental programs on the basis of the chromatin state. |
23260670 | Gambogic acid is a tissue-specific proteasome inhibitor in vitro and in vivo. | Gambogic acid (GA) is a natural compound derived from Chinese herbs that has been approved by the Chinese Food and Drug Administration for clinical trials in cancer patients; however, its molecular targets have not been thoroughly studied. Here, we report that GA inhibits tumor proteasome activity, with potency comparable to bortezomib but much less toxicity. First, GA acts as a prodrug and only gains proteasome-inhibitory function after being metabolized by intracellular CYP2E1. Second, GA-induced proteasome inhibition is a prerequisite for its cytotoxicity and anticancer effect without off-targets. Finally, because expression of the CYP2E1 gene is very high in tumor tissues but low in many normal tissues, GA could therefore produce tissue-specific proteasome inhibition and tumor-specific toxicity, with clinical significance for designing novel strategies for cancer treatment. |
23260671 | Polyaniline coated micro-capillaries for continuous flow analysis of aqueous solutions. | The inner walls of fused silica micro-capillaries were successfully coated with polyaniline nanofibres using the "grafting" approach. The optical response of polyaniline coatings was evaluated during the subsequent redoping-dedoping processes with hydrochloric acid and ammonia solutions, respectively, that were passed inside the micro-capillary in continuous flow. The optical absorbance of the polyaniline coatings was measured and analysed in the wavelength interval of [300-850 nm] to determine its optical sensitivity to different concentrations of ammonia. It was found that the optical properties of polyaniline coatings change in response to ammonia solutions in a wide concentration range from 0.2 ppm to 2000 ppm. The polyaniline coatings employed as a sensing material for the optical detection of aqueous ammonia have a fast response time and a fast regeneration time of less than 5 s at room temperature. The coating was fully characterised by scanning electron microscopy, Raman spectroscopy, absorbance measurements and kinetic studies. The response of the coatings showed very good reproducibility, demonstrating that this platform can be used for the development of micro-capillary integrated sensors based on the inherited sensing properties of polyaniline. |
23260669 | Induction of CD8+ regulatory T cells protects macaques against SIV challenge. | Efforts to develop a vaccine against HIV have so far met with limited success. Given that CD4(+) T cell activation drives the initial burst of viral replication, we explored in macaques whether an oral vaccine comprised of Lactobacillus plantarum, a commensal bacterium that favors immune tolerance, and inactivated simian immunodeficiency virus mac239 (SIVmac239) would induce CD4(+) T cell unresponsiveness/tolerance toward SIV antigens and thereby prevent the establishment of SIV infection. The tolerogenic vaccine induced MHC-Ib/E-restricted CD8(+) regulatory T cells (Tregs) that suppressed SIV-harboring CD4(+) T cell activation and ex vivo SIV replication in 15 of 16 animals without inducing SIV-specific antibodies or cytotoxic T lymphocytes. Of 16 macaques that were intrarectally challenged with SIVmac239 or heterologous strain SIVB670, 15 were sterilely protected. In four macaques that were rechallenged intravenously, plasma SIV levels peaked slightly and then dropped to undetectable levels, although the animals subsequently harbored intracellular SIV DNA. Infusion of CD8 antibodies confirmed the role of CD8(+) Tregs in preventing/suppressing SIV in vivo. These findings suggest a new avenue of research toward developing an HIV-1 vaccine. |
23260667 | MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response. | Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes. |
23260666 | Highly coordinated proteome dynamics during reprogramming of somatic cells to pluripotency. | Generation of induced pluripotent stem cells (iPSCs) is a process whose mechanistic underpinnings are only beginning to emerge. Here, we applied in-depth quantitative proteomics to monitor proteome changes during the course of reprogramming of fibroblasts to iPSCs. We uncover a two-step resetting of the proteome during the first and last 3 days of reprogramming, with multiple functionally related proteins changing in expression in a highly coordinated fashion. This comprised several biological processes, including changes in the stoichiometry of electron transport-chain complexes, repressed vesicle-mediated transport during the intermediate stage, and an EMT-like process in the late phase. In addition, we demonstrate that the nucleoporin Nup210 is essential for reprogramming by its permitting of rapid cellular proliferation and subsequent progression through MET. Along with the identification of proteins expressed in a stage-specific manner, this study provides a rich resource toward an enhanced mechanistic understanding of cellular reprogramming. |
23260665 | Genetic dissection of neurotrophin signaling through the p75 neurotrophin receptor. | Structural determinants underlying signaling specificity in the tumor necrosis factor receptor superfamily (TNFRSF) are poorly characterized, and it is unclear whether different signaling outputs can be genetically dissociated. The p75 neurotrophin receptor (p75(NTR)), also known as TNFRSF16, is a key regulator of trophic and injury responses in the nervous system. Here, we describe a genetic approach for dissecting p75(NTR) signaling and deciphering its underlying logic. Structural determinants important for regulation of cell death, NF-κB, and RhoA pathways were identified in the p75(NTR) death domain (DD). Proapoptotic and prosurvival pathways mapped onto nonoverlapping epitopes, demonstrating that different signaling outputs can be genetically separated in p75(NTR). Dissociation of c-Jun kinase (JNK) and caspase-3 activities indicated that JNK is necessary but not sufficient for p75(NTR)-mediated cell death. RIP2 recruitment and RhoGDI release were mechanistically linked, indicating that competition for DD binding underlies crosstalk between NF-κB and RhoA pathways in p75(NTR) signaling. These results provide insights into the logic of p75(NTR) signaling and pave the way for a genetic dissection of p75(NTR) function and physiology. |
23260664 | Telomere length correlates with life span of dog breeds. | Telomeric DNA repeats are lost as normal somatic cells replicate. When telomeres reach a critically short length, a DNA damage signal is initiated, inducing cell senescence. Some studies have indicated that telomere length correlates with mortality, suggesting that telomere length contributes to human life span; however, other studies report no correlation, and thus the issue remains controversial. Domestic dogs show parallels in telomere biology to humans, with similar telomere length, telomere attrition, and absence of somatic cell telomerase activity. Using this model, we find that peripheral blood mononuclear cell (PBMC) telomere length is a strong predictor of average life span among 15 different breeds (p < 0.0001), consistent with telomeres playing a role in life span determination. Dogs lose telomeric DNA ~10-fold faster than humans, which is similar to the ratio of average life spans between these species. Breeds with shorter mean telomere lengths show an increased probability of death from cardiovascular disease, which was previously correlated with short telomere length in humans. |
23260663 | Human telomeres are tethered to the nuclear envelope during postmitotic nuclear assembly. | Telomeres are essential for nuclear organization in yeast and during meiosis in mice. Exploring telomere dynamics in living human cells by advanced time-lapse confocal microscopy allowed us to evaluate the spatial distribution of telomeres within the nuclear volume. We discovered an unambiguous enrichment of telomeres at the nuclear periphery during postmitotic nuclear assembly, whereas telomeres were localized more internally during the rest of the cell cycle. Telomere enrichment at the nuclear rim was mediated by physical tethering of telomeres to the nuclear envelope, most likely via specific interactions between the shelterin subunit RAP1 and the nuclear envelope protein Sun1. Genetic interference revealed a critical role in cell-cycle progression for Sun1 but no effect on telomere positioning for RAP1. Our results shed light on the dynamic relocalization of human telomeres during the cell cycle and suggest redundant pathways for tethering telomeres to the nuclear envelope. |
23260662 | Lsd1 and lsd2 control programmed replication fork pauses and imprinting in fission yeast. | In the fission yeast Schizosaccharomyces pombe, a chromosomal imprinting event controls the asymmetric pattern of mating-type switching. The orientation of DNA replication at the mating-type locus is instrumental in this process. However, the factors leading to imprinting are not fully identified and the mechanism is poorly understood. Here, we show that the replication fork pause at the mat1 locus (MPS1), essential for imprint formation, depends on the lysine-specific demethylase Lsd1. We demonstrate that either Lsd1 or Lsd2 amine oxidase activity is required for these processes, working upstream of the imprinting factors Swi1 and Swi3 (homologs of mammalian Timeless and Tipin, respectively). We also show that the Lsd1/2 complex controls the replication fork terminators, within the rDNA repeats. These findings reveal a role for the Lsd1/2 demethylases in controlling polar replication fork progression, imprint formation, and subsequent asymmetric cell divisions. |
23260661 | Listeriosis outbreaks and associated food vehicles, United States, 1998-2008. | Listeria monocytogenes, a bacterial foodborne pathogen, can cause meningitis, bacteremia, and complications during pregnancy. This report summarizes listeriosis outbreaks reported to the Foodborne Disease Outbreak Surveillance System of the Centers for Disease Control and Prevention during 1998-2008. The study period includes the advent of PulseNet (a national molecular subtyping network for outbreak detection) in 1998 and the Listeria Initiative (enhanced surveillance for outbreak investigation) in 2004. Twenty-four confirmed listeriosis outbreaks were reported during 1998-2008, resulting in 359 illnesses, 215 hospitalizations, and 38 deaths. Outbreaks earlier in the study period were generally larger and longer. Serotype 4b caused the largest number of outbreaks and outbreak-associated cases. Ready-to-eat meats caused more early outbreaks, and novel vehicles (i.e., sprouts, taco/nacho salad) were associated with outbreaks later in the study period. These changes may reflect the effect of PulseNet and the Listeria Initiative and regulatory initiatives designed to prevent contamination in ready-to-eat meat and poultry products. |
23260660 | Uncovering a region of heat shock protein 90 important for client binding in E. coli and chaperone function in yeast. | The heat shock protein 90 (Hsp90) family of heat shock proteins is an abundantly expressed and highly conserved family of ATP-dependent molecular chaperones. Hsp90 facilitates remodeling and activation of hundreds of proteins. In this study, we developed a screen to identify Hsp90-defective mutants in E. coli. The mutations obtained define a region incorporating residues from the middle and C-terminal domains of E. coli Hsp90. The mutant proteins are defective in chaperone activity and client binding in vitro. We constructed homologous mutations in S. cerevisiae Hsp82 and identified several that caused defects in chaperone activity in vivo and in vitro. However, the Hsp82 mutant proteins were less severely defective in client binding to a model substrate than the corresponding E. coli mutant proteins. Our results identify a region in Hsp90 important for client binding in E. coli Hsp90 and suggest an evolutionary divergence in the mechanism of client interaction by bacterial and yeast Hsp90. |
23260658 | RecA-promoted, RecFOR-independent progressive disassembly of replisomes stalled by helicase inactivation. | In all organisms, replication impairment is a recognized source of genomic instability, raising an increasing interest in the fate of inactivated replication forks. We used Escherichia coli strains with a temperature-inactivated replicative helicase (DnaB) and in vivo single-molecule microscopy to quantify the detailed molecular processing of stalled replication forks. After helicase inactivation, RecA binds to blocked replication forks and is essential for the rapid release of hPol III. The entire holoenzyme is disrupted little by little, with some components lost in few minutes, while others are stable in 70% of cells for at least 1 hr. Although replisome dissociation is delayed in a recA mutant, it is not affected by RecF or RecO inactivation. RecFOR are required for full RecA filaments formation, and we propose that polymerase clearance can be catalyzed by short, RecFOR-independent RecA filaments. Our results identify a function for the universally conserved, central recombination protein RecA. |
23260657 | Noncanonical role of the 9-1-1 clamp in the error-free DNA damage tolerance pathway. | Damaged DNA is an obstacle during DNA replication and a cause of genome instability and cancer. To bypass this problem, eukaryotes activate DNA damage tolerance (DDT) pathways that involve ubiquitylation of the DNA polymerase clamp proliferating cell nuclear antigen (PCNA). Monoubiquitylation of PCNA mediates an error-prone pathway by recruiting translesion polymerases, whereas polyubiquitylation activates an error-free pathway that utilizes undamaged sister chromatids as templates. The error-free pathway involves recombination-related mechanisms; however, the factors that act along with polyubiquitylated PCNA remain largely unknown. Here we report that the PCNA-related 9-1-1 complex, which is typically linked to checkpoint signaling, participates together with Exo1 nuclease in error-free DDT. Notably, 9-1-1 promotes template switching in a manner that is distinct from its canonical checkpoint functions and uncoupled from the replication fork. Our findings thus reveal unexpected cooperation in the error-free pathway between the two related clamps and indicate that 9-1-1 plays a broader role in the DNA damage response than previously assumed. |
23260656 | Structural determinants of RGS-RhoGEF signaling critical to Entamoeba histolytica pathogenesis. | G protein signaling pathways, as key components of physiologic responsiveness and timing, are frequent targets for pharmacologic intervention. Here, we identify an effector for heterotrimeric G protein α subunit (EhGα1) signaling from Entamoeba histolytica, the causative agent of amoebic colitis. EhGα1 interacts with this effector and guanosine triphosphatase-accelerating protein, EhRGS-RhoGEF, in a nucleotide state-selective fashion. Coexpression of EhRGS-RhoGEF with constitutively active EhGα1 and EhRacC leads to Rac-dependent spreading in Drosophila S2 cells. EhRGS-RhoGEF overexpression in E. histolytica trophozoites leads to reduced migration toward serum and lower cysteine protease activity, as well as reduced attachment to, and killing of, host cells. A 2.3 Å crystal structure of the full-length EhRGS-RhoGEF reveals a putative inhibitory helix engaging the Dbl homology domain Rho-binding surface and the pleckstrin homology domain. Mutational analysis of the EhGα1/EhRGS-RhoGEF interface confirms a canonical "regulator of G protein signaling" domain rather than a RhoGEF-RGS ("rgRGS") domain, suggesting a convergent evolution toward heterotrimeric and small G protein cross-talk. |
23260655 | Leukemia fusion target AF9 is an intrinsically disordered transcriptional regulator that recruits multiple partners via coupled folding and binding. | Mixed lineage leukemia (MLL) fusion proteins cause oncogenic transformation of hematopoietic cells by constitutive recruitment of elongation factors to HOX promoters, resulting in overexpression of target genes. The structural basis of transactivation by MLL fusion partners remains undetermined. We show that the ANC1 homology domain (AHD) of AF9, one of the most common MLL translocation partners, is intrinsically disordered and recruits multiple transcription factors through coupled folding and binding. We determined the structure of the AF9 AHD in complex with the elongation factor AF4 and show that aliphatic residues, which are conserved in each of the AF9 binding partners, form an integral part of the hydrophobic core of the complex. Nuclear magnetic resonance relaxation measurements show that AF9 retains significant dynamic behavior which may facilitate exchange between disordered partners. We propose that AF9 functions as a signaling hub that regulates transcription through dynamic recruitment of cofactors in normal hematopoiesis and in acute leukemia. |
23260654 | Crystal structure of the O(2)-tolerant membrane-bound hydrogenase 1 from Escherichia coli in complex with its cognate cytochrome b. | We report the 3.3 Å resolution structure of dimeric membrane-bound O(2)-tolerant hydrogenase 1 from Escherichia coli in a 2:1 complex with its physiological partner, cytochrome b. From the short distance between distal [Fe(4)S(4)] clusters, we predict rapid transfer of H(2)-derived electrons between hydrogenase heterodimers. Thus, under low O(2) levels, a functional active site in one heterodimer can reductively reactivate its O(2)-exposed counterpart in the other. Hydrogenase 1 is maximally expressed during fermentation, when electron acceptors are scarce. These conditions are achieved in the lower part of the host's intestinal tract when E. coli is soon to be excreted and undergo an anaerobic-to-aerobic metabolic transition. The apparent paradox of having an O(2)-tolerant hydrogenase expressed under anoxia makes sense if the enzyme functions to keep intracellular O(2) levels low by reducing it to water, protecting O(2)-sensitive enzymes during the transition. Cytochrome b's main role may be anchoring the hydrogenase to the membrane. |
23260652 | Trends in the levels of Escherichia coli in commercially harvested bivalve shellfish from England and Wales, 1999-2008. | Temporal trends in Escherichia coli concentrations in bivalve shellfish were examined using data collected from 57 production areas around the coast of England and Wales during 1999-2008. Downward trends were detected in annual geometric means of E. coli in shellfish from 12% of the sampling points. The percentage of class B areas (E. coli ≤ 4600/100 g shellfish in 90% of samples) increased from 69% to 86% during the 10-year period. The improvement in the microbial quality of shellfish is associated with sewerage improvement schemes largely implemented during 2000-2005. Upward trends were detected in 9% of the points. The causes of these increases are not known. It is recommended that quantitative sanitary profiling of shellfish waters and cost-benefit appraisal over long-term planning horizons are considered as part of sewerage investment programmes under the Water Framework Directive. This would allow greater scope to secure protection and improvement of shellfish water quality. |
23260651 | Spring plankton community structure and distribution in the north and south coasts of Sfax (Tunisia) after north coast restoration. | The first phase of the Taparura Project aimed at restoring the north coast of Sfax (Tunisia), highly polluted by phosphate industry and uncontrolled phosphogypsum dumping. Before restoration of the north coast of Sfax, we investigated the state of the ecosystem in related coastal waters. To establish the impact of the Taparura Project, we conducted a similar study both after restoration. To discriminate natural changes over time, we extended the study to the south coast of Sfax, submitted to the same industrial pressure but not yet restored. The present study, conducted in May 2010 at 36 stations (18 on each coast, north and south), covered the spatial distribution of the microbial assemblage, nutrients, and abiotic parameters by collecting seawater samples at the surface and the water-sediment interface. Results revealed a striking difference between the two coasts regarding pH, with strong acidification of seawater in the south, likely generated by industrial activity. Suspended matter was higher in the north than in the south. Flow cytometry analysis of ultraphytoplankton (<10 μm) resolved six groups (Prochlorococcus, Synechococcus, nanoeukaryotes and three distinct subgroups within picoeukaryotes). In addition to these autotrophic groups, two unknown groups were characterised on the south coast. Heterotrophic prokaryotes were resolved into three groups, labelled LNA (low nucleic acid content), HNA1 and HNA2 (high nucleic acid content). Prochloroccocus, pico-nano-microphytoplankton, heterotrophic prokaryotes and ciliates were more abundant in the north, whereas Synechococcus and unknown species were more abundant in the south where chl a concentration was also higher. The results show that restoration had positive effects on the microbial assemblage of the north coast; they also highlight the strong acidification still prevalent in the south that may be responsible for the lower development of most phytoplankton groups and the occurrence of unknown species. The case for restoration of the city's south coast is also reinforced. |
23260650 | A baseline study of tropical coastal water quality in Port Dickson, Strait of Malacca, Malaysia. | Tidal variation in tropical coastal water plays an important role on physicochemical characteristics and nutrients concentration. Baseline measurements were made for nutrients concentration and physicochemical properties of coastal water, Port Dickson, Malaysia. pH, temperature, oxidation reduction potential, salinity and electrical conductivity have high values at high tides. Principal Components Analysis (PCA) was used to understand spatial variation of nutrients and physicochemical pattern of Port Dickson coastal water at high and low tide. Four principal components of PCA were extracted at low and high tides. Positively loaded nutrients with negative loadings of DO, pH and ORP in PCA outputs indicated nutrients contribution related with pollution sources. This study output will be a baseline frame for future studies in Port Dickson involving water and sediment samples. Water and sediment samples of future monitoring studies in Port Dickson coastal water will help in understanding of coastal water chemistry and pollution sources. |
23260649 | Reciprocal experimental transplantations to assess effects of organic enrichment on the recolonization of benthic macrofauna in a subtropical estuary. | Coastal benthic habitats are usually in a state of continuous recolonization as a consequence of natural disturbances or human activities. Recolonization patterns can be strongly affected by the quality of the sediment. We evaluated herein the macrobenthic recolonization of organically enriched sediments through a manipulative experiment involving reciprocal transplants between contaminated and non-contaminated intertidal areas. Regardless of the experimental treatments, the density of the polychaete Capitella sp. was extremely high in the contaminated area as well as the density of the gastropod Cylichna sp. in the non-contaminated area. We rejected the hypothesis that differences in sediment quality would determine macrofaunal recolonization at least in the considered scales of space in meters and time in weeks. The recolonization process in a subtropical estuarine environment was strongly dependent on the migration of adults present in the sediments adjacent to the experimental units. |
23260648 | Broad-scale patterns of tissue-δ15N and tissue-N indices in frondose Ulva spp.; developing a national baseline indicator of nitrogen-loading for coastal New Zealand. | A survey of tissue-δ(15)N and tissue-N values in the green macroalga, Ulva, was conducted around the coast of New Zealand to determine if these indices could be used as indicators of anthropogenic nutrient loading in coastal waters. In addition, data from four case studies showed temporal and spatial responses of tissue-δ(15)N and tissue-N in Ulva to significant terrestrial nutrient inputs. Tissue-δ(15)N in Ulva from 'natural' exposed coastal sites showed a relatively narrow baseline range of values (6.6±0.1-8.8±0.1‰) in both summer and winter that was consistent throughout New Zealand. Departures in Ulva tissue-δ(15)N ratios outside this range, particularly when coupled with high (>3.1%) tissue-N values, indicate significant contributions of terrestrially-derived nitrogen to coastal seawater. We note that tissue-N content is also affected by exposure, light and season; however provided such factors are taken into account Ulva can be a cost-effective indicator of relative changes in both source and amount of nitrogen-loading. |
23260647 | Macrobenthos habitat potential mapping using GIS-based artificial neural network models. | This paper proposes and tests a method of producing macrobenthos habitat potential maps in Hwangdo tidal flat, Korea based on an artificial neural network. Samples of macrobenthos were collected during field work, and eight control factors were compiled as a spatial database from remotely sensed data and GIS analysis. The macrobenthos habitat potential maps were produced using an artificial neural network model. Macrobenthos habitat potential maps were made for Macrophthalmus dilatatus, Cerithideopsilla cingulata, and Armandia lanceolata. The maps were validated by compared with the surveyed habitat locations. A strong correlation between the potential maps and species locations was revealed. The validation result showed average accuracies of 74.9%, 78.32%, and 73.27% for M. dilatatus, C. cingulata, and A. lanceolata, respectively. A GIS-based artificial neural network model combined with remote sensing techniques is an effective tool for mapping the areas of macrobenthos habitat potential in tidal flats. |
23260646 | A baseline study of levels of mercury, arsenic, cadmium and lead in Northeast Arctic cod (Gadus morhua) from different parts of the Barents Sea. | This study is one of several baseline studies that will provide basic and reliable information about the content of undesirable substances in important species of fish caught in Norwegian waters. Concentrations of metals in the muscle and liver of more than 800 Northeast Arctic cod caught at 32 sites in the Barents Sea are reported. The highest concentration of both mercury in the muscle and cadmium in the liver was found in cod caught in the western part of the Barents Sea, while the highest concentration of total arsenic was found in cod from the eastern part. The arsenic concentrations varied greatly among individual fish, ranging from 0.3 to 170 mg kg(-1) wet weight in the muscle. Such high levels of total arsenic have never previously been reported in any fish, and the primary factor for these high concentrations is likely to be the shrimp in the cod diet. |
23260630 | Variations of 210Po and 210Pb concentration in mussels (Mytilus galloprovincialis) from Didim and Izmir Bay (Turkish coast of Aegean Sea). | In this study, the activity concentrations of (210)Po and (210)Pb were determined in mussels (Mytilus galloprovincialis) collected from Didim and Izmir Bay (Turkish coast of Aegean Sea) during the period of April 2006-March 2007. The concentrations activity of (210)Po were determined spectroscopically through its 5.30 MeV alpha particle emission, using (209)Po as an internal tracer. The (210)Pb activity concentrations were determined from the ingrowth of (210)Po, assuming zero initial (210)Po activity. The results of (210)Po and (210)Pb activity concentrations were found to vary between 34 ± 9 and 1855 ± 98 Bq kg(-1) dry weight and ND (lower than limit of detection) - 64 ± 6 Bq kg(-1) dry weight, respectively. (210)Po/(210)Pb ratio ranged between 1.00 and 106.87. The highest (210)Po activities were found in mussels collected from Didim. |
23260628 | [Single-dose intraincisional levobupivacaine infiltration in caesarean postoperative analgesia: a placebo-controlled double-blind randomized trial]. | The efficacy of single-dose intraincisional infiltration with levobupivacaine in postoperative analgesia and chronic pain after caesarean sections is unknown. A placebo-controlled double-blind randomized trial. After ethical approval, and written inform consent, 140 women scheduled for a caesarean section were randomly assigned and received 30mL of levobupivacaine 0.5% (L group) or saline (placebo-P group) into their wound. The primary endpoint was morphine consumption (using intravenous morphine patient-controlled analgesia) for the first 24h after surgery. At 1h to 48h, side effects, pain at rest and pain 2months later were recorded. All included patients had similar demographic and surgical characteristics. The morphine consumption was significantly lower in the L group at h6, h8 and h12 (considering both total intake and each request). At h4, the mean total morphine consumption was 25 (12) mg in the L group versus 31 (14) mg in the P group (P=0.05). Time until discharge and side effects including nausea-vomiting (14 vs 20%), wound scar complications (6 vs 8%) and chronic pain after 2months (25% in both groups complained of small pain, and 75% no pain) were similar between the two groups (P>0.05). Single-dose local infiltration of levobupivacaine 0.5% reduced opioid requirement at 12h, with no difference after 24h. www.clinicaltrials.com, number: NCT00621907. |
23260626 | Repeated, long-term cycling of putative stem cells between niches in a basal chordate. | The mechanisms that sustain stem cells are fundamental to tissue maintenance. Here, we identify "cell islands" (CIs) as a niche for putative germ and somatic stem cells in Botryllus schlosseri, a colonial chordate that undergoes weekly cycles of death and regeneration. Cells within CIs express markers associated with germ and somatic stem cells and gene products that implicate CIs as signaling centers for stem cells. Transplantation of CIs induced long-term germline and somatic chimerism, demonstrating self-renewal and pluripotency of CI cells. Cell labeling and in vivo time-lapse imaging of CI cells reveal waves of migrations from degrading CIs into developing buds, contributing to soma and germline development. Knockdown of cadherin, which is highly expressed within CIs, elicited the migration of CI cells to circulation. Piwi knockdown resulted in regeneration arrest. We suggest that repeated trafficking of stem cells allows them to escape constraints imposed by the niche, enabling self-preservation throughout life. |
23260627 | Seropositivity for influenza A(H1N1)pdm09 virus among frontline health care personnel. | Seroprevalence of antibodies to influenza A(H1N1)pdm09 virus among 193 emergency department health care personnel was similar among 147 non-health care personnel (odds ratio 1.4, 95% CI 0.8-2.4). Working in an acute care setting did not substantially increase risk for virus infection above risk conferred by community-based exposures. |
23260625 | Biochemical membrane lipidomics during Drosophila development. | Lipids play critical roles in energy homeostasis, membrane structure, and signaling. Using liquid chromatography and mass spectrometry, we provide a comprehensive semiquantification of lipids during the life cycle of Drosophila melanogaster (230 glycerophospholipids, 210 sphingolipids, 6 sterols and sterol esters, and 60 glycerolipids) and obtain biological insights through this biochemical resource. First, we find a high and constant triacylglycerol-to-membrane lipid ratio during pupal stage, which is nonobvious in the absence of nutrient uptake and tissue remodeling. Second, sphingolipids undergo specific changes in headgroup (glycosylation) and tail configurations (unsaturation and hydroxylation on sphingoid base and fatty acyls, respectively), which correlate with gene expression of known (GlcT/CG6437; FA2H/ CG30502) and putative (Cyt-b5-r/CG13279) enzymes. Third, we identify a gender bias in phosphoethanolamine-ceramides as a lead for future investigation into sexual maturation. Finally, we partially characterize ghiberti, required for male meiotic cytokinesis, as a homolog of mammalian serine palmitoyltransferase. |
23260624 | A preceptorship programme for newly qualified nurses: a study of preceptees' perceptions. | This paper presents the evaluation of a preceptorship programme for newly-qualified nurses (NQNs) to determine preceptee engagement with the preceptorship programme, and the impact, value and sustainability of the programme from the preceptees' perspectives. The literature suggests that NQNs find the transition from student to qualified nurse to be stressful and that preceptorship can reduce this stress and promote adaptation to the new role. This study took place in one NHS Healthcare Trust in South West London, UK. Ninety NQNs were invited to participate in the study and the response rate was 48.9% (n=44). The study took place in 2011. Evaluative research design was used incorporating a fourfold evaluation framework of preceptee engagement, impact, value and sustainability (Ooms et al., 2011). This was a mixed methods study. Qualitative and quantitative data were collected through questionnaires, reflective journals and through personal audio recordings made by the preceptees. Quantitative data were analysed through descriptive statistics and t-tests, and Cronbach's alpha coefficient was used to assess reliability of impact and value scales. In addition analysis of open-ended questions and qualitative data was undertaken using the Framework Method of analysis. Findings show that preceptee engagement in the programme was high and preceptorship was highly valued by the majority of preceptees (85%). Preceptors played a positive role in terms of alleviating stress. Preceptorship impacted positively on preceptees in terms of development of communication skills and clinical skills, and role, personal and professional development. In addition, preceptees felt that the programme was of value despite acknowledging difficulties in making time to meet with preceptors. Preceptees also indicated that they would wish to be preceptors in the future and that they would recommend preceptorship to all nurses who are either newly qualified or new in role. Preceptees judged the preceptorship programme positively for engagement, impact, value and sustainability. The study is unique when mapped against other research studies as it explores a breadth of evaluative issues not found in other preceptorship studies, e.g. engagement, impact, value and sustainability of preceptorship. The study adds insights about sustainability of preceptorship programmes and expectations of competence of NQNs that do not appear in previous literature about preceptorship. |
23260623 | Mastering the professional role as a newly graduated registered nurse. | Professional development is a process starting during undergraduate education and continuing throughout working life. A new nurse's transition from school to work has been described as difficult. This study aims to develop a model describing the professional development of new nurses during their first years of work. To develop this model, constant comparative analyses were performed. The method was a qualitative study of survey data on 330 registered nurses. The results showed that mastering the professional role was the result of an ongoing process building on the nurse's experiences and interactions with the surrounding environment. The professional developmental process involves the following interrelated sub-processes: evaluating and re-evaluating educational experiences, developing professional self-efficacy and developing clinical competence. These sub-processes are influenced by the following factors: social values and norms, healthcare organization, management of new nurses, co-workers, patients and significant others and the nurse's own family and friends. These factors affect professional development directly, indirectly or as mediating influences and can lead to possible outcomes, as new nurses choose to remain in or leave the profession. The results underscore the importance of developing a professional nursing role within the new working context. To facilitate this professional development, new nurses need support from their nursing-school educators and their healthcare employers. The model described here will be the subject of further measurement and testing. |
23260622 | Constructing and validating a global student-centered nursing curriculum learning efficacy scale: a confirmatory factor analysis. | Previous evidence-based studies have lacked a comprehensive student-centered scale to measure the learning efficacy of pre-registered nursing students. This study developed and validated a global scale for measuring learning efficacy among pre-registered nurses in Taiwan. Evaluated nursing courses included fundamental nursing, medical-surgical nursing, maternal-newborn nursing, pediatric nursing, psychiatric nursing, and community health nursing. All participants had previously completed the nursing professional curricula. This study comprised four phases, which were design of the initial study questionnaire, testing of the validity of the responses of experts to the questionnaire, exploratory factor analysis based on random sampling, and confirmatory factor analysis based on a large-scale investigation. The content validity index for the questionnaire was .89. Item analysis results yielded a Cronbach's α coefficient of between .90 and .92. Item-total correlation coefficients ranged from .51 to .76. The critical ratio, obtained from t-test results, ranged from 6.07 to 9.96. Exploratory factor analysis revealed that factor loadings for individual items ranged from .46 to .96, and eigenvalues ranged from 1.43 to 8.19. The three factors "learning preparation," "advancement of competency," and "learning evaluation" explained 63.5% of total factor loading. In the confirmatory factor analysis, the overall internal consistency reliability coefficient was .95; convergent reliability was .96, and convergent validity was .59. Evaluation scales demonstrated well construct validity and goodness-of-fit for the model. The comprehensive student-centered evaluation scale revealed rigorous construct validity. This scale can serve as an index of learning effectiveness in professional nursing curricula. |
23260620 | Promoting student learning and increasing organizational capacity to host students in residential aged care: a mixed method research study. | In Australia, the Federal government's agenda to increase clinical training places to address the forecast shortfall of nurses is driving innovation in clinical education. A student leadership model of clinical education, named the Student Nurse Led Ward model, was designed for the aged care context to provide a high number of clinical placements for pre-service Bachelor of Nursing students in an under-utilized clinical education setting. The research aimed to determine the viability of the innovation by (1) developing a preliminary understanding of what students were learning and (2) exploring stakeholders' perceptions about student learning. A mixed methods design included an ageing knowledge test and ageing attitudes survey, both administered before and after the placement, student narratives of a learning event written after the placement, as well as focus group and individual interviews with stakeholders. Three residential aged care facilities partnering with one university in one Australian jurisdiction. Included 35 of the 45 students who began placement in the aged care facilities during one semester, a convenience sample of 15 staff and each of the managers and educators from the three agencies. Descriptive statistical analysis of student pre-post knowledge test and attitude survey, hermeneutic analysis of student narratives, and content analysis of individual and group interview data. There was an increase in student knowledge around sensory changes, delirium, and drug reactions in older people. There was a slight increase in students' expression of ageist attitudes following the clinical experience. The clinical educator position was considered to be critical to the success of the model. This Student Nurse Led Ward model is a viable model to increase clinical placements, with preliminary evidence in this study suggesting that students benefit through increased knowledge, understanding and capacity to work with older people. |
23260621 | Developing global citizenship online: an authentic alternative to overseas clinical placement. | This paper presents the findings of a pilot project to develop and evaluate an international nursing module delivered using a collaborative online platform between nursing programmes in Scotland, USA and Finland. The purpose of the project was to provide an authentic international nursing experience for nursing students, allowing them to explore and contrast the nursing and health care issues in an international context. The pilot cohort ran in September 2011 with a total of 22 students with a mix of students from both undergraduate and postgraduate programmes. A mixed methods research design was used to evaluate the students' experience using an anonymous online questionnaire and the collection of testimonials from students based on their experience. The results demonstrated high levels of satisfaction with the learning experience. Four key themes-learning together, widening horizons, developing autonomy and learning beyond frontiers-emerged from the qualitative data. Developing confidence from the shared learning experience has real implications for the global mobility of the nursing workforce as it helps to prepare nurses for a career beyond their own country's borders. The pilot module has clearly demonstrated that the use of Web 2.0 technology in the forms of a wiki may effectively be employed to provide an online learning environment to allow cross institutional learning. |
23260619 | Preparing students for graduate study: an eLearning approach. | This paper describes the development and preliminary evaluation of an eLearning program intended to provide incoming nursing students with the basic knowledge, skills and abilities needed to succeed in graduate-level, online coursework. Using Mayer's principles (2008) for the effective design of multimedia instruction, an open-access, self-directed, online program was developed. The Graduate School Boot Camp includes five online modules focused on learning strategies and time management, academic writing, technology, research, and library skills. To motivate and engage learners, the program integrates a fun, graphical sports theme with audiovisual presentations, examples, demonstrations and practice exercises. Learners begin with a self-assessment based on the Motivated Strategies for Learning Questionnaire or MSLQ (Pintrich et al., 1993). To assess change in knowledge levels before and after completing the program, learners take a pre-test and post-test. Preliminary findings indicate that the students found the information relevant and useful. They enjoyed the self-paced, multimedia format, and liked the option to return to specific content later. This innovative program offers a way to prepare students proactively, and may prove useful in identifying students at risk and connecting them with the appropriate resources to facilitate successful program completion. |
23260618 | A randomized controlled trial of the effects of brief mindfulness meditation on anxiety symptoms and systolic blood pressure in Chinese nursing students. | Previous studies suggested that mindfulness meditation effectively reduced stress-related anxiety and depression symptoms, but no research has evaluated the efficacy of mindfulness meditation in nurses and nursing students in China. To evaluate the effects of brief mindfulness meditation on the anxiety and depression symptoms and autonomic nervous system activity in Chinese nursing students. A randomized controlled trial. A medical university in Guangzhou, China. One hundred and five nursing students were randomly approached by email and seventy-two responded. Sixty recruited students were randomized into meditation and control group (n=30 each) after screening and exclusion due to factors known to influence mood ratings and autonomic nervous system measures. The meditation group performed mindfulness meditation 30 min daily for 7 consecutive days. The control group received no intervention except pre-post treatment measurements. The Self-Rating Anxiety Scale and Self-Rating Depression Scale were administered to participants, and heart rate and blood pressure were measured. Pre- and post-treatment data were analyzed using repeated-measures analysis of variance. Differences between pre- and post-treatment Self-Rating Anxiety Scale scores were significantly larger in the meditation group than in the control group, but no similar effect was observed for Self-Rating Depression Scale scores. Systolic blood pressure was reduced more after the intervention in the meditation group than in the control group, with an average reduction of 2.2 mmHg. A moderate level of anxiety was associated with the maximum meditation effect. Brief mindfulness meditation was beneficial for Chinese nursing students in reducing anxiety symptoms and lowering systolic blood pressure. Individuals with moderate anxiety are most likely to benefit from a short-term mindfulness meditation program. |
23260617 | The experience of end of life care simulation at a rural Australian University. | Providing end of life care is a challenging and anxiety provoking prospect for many undergraduate nursing students and many students report a lack of preparedness in providing care. The limited availability of appropriate clinical placements limits the opportunities for nursing students to gain experience in end of life care. Advances in simulation techniques using high fidelity mannequins enable the mimicking of complex patient scenarios such as cessation of life in the provision of end of life care. A group of nursing academics at a rural Australian University designed, developed and implemented end of life care simulation to a group of 3rd year nursing students. The aim of this paper is to report on the evaluation of this educational innovation. Five major themes were identified through analysis of student evaluations: 1) Linking of theory to practice; 2) Approaching families of dying patients; 3) An encounter with death; 4) 'Hands on' experience in a 'protected environment'; and 5) Importance of post simulation discussion and debriefing. End of life care simulation has provided a valuable experience that can be difficult to obtain in clinical practice settings. However, the challenges discussed in this paper need to be taken into consideration for future use. |
23260616 | Impact of peer teaching on nursing students: perceptions of learning environment, self-efficacy, and knowledge. | Peer teaching has been shown to enhance student learning and levels of self efficacy. The purpose of the current study was to examine the impact of peer-teaching learning experiences on nursing students in roles of tutee and tutor in a clinical lab environment. This study was conducted over a three-semester period at a South Central University that provides baccalaureate nursing education. Over three semesters, 179 first year nursing students and 51 third year nursing students participated in the study. This mixed methods study, through concurrent use of a quantitative intervention design and qualitative survey data, examined differences during three semesters in perceptions of a clinical lab experience, self-efficacy beliefs, and clinical knowledge for two groups: those who received peer teaching-learning in addition to faculty instruction (intervention group) and those who received faculty instruction only (control group). Additionally, peer teachers' perceptions of the peer teaching learning experience were examined. Results indicated positive response from the peer tutors with no statistically significant differences for knowledge acquisition and self-efficacy beliefs between the tutee intervention and control groups. In contrast to previous research, students receiving peer tutoring in conjunction with faculty instruction were statistically more anxious about performing lab skills with their peer tutor than with their instructors. Additionally, some students found instructors' feedback moderately more helpful than their peers and increased gains in knowledge and responsibility for preparation and practice with instructors than with peer tutors. The findings in this study differ from previous research in that the use of peer tutors did not decrease anxiety in first year students, and no differences were found between the intervention and control groups related to self efficacy or cognitive improvement. These findings may indicate the need to better prepare peer tutors, and research should be conducted using more complex skills. |
23260615 | The neural basis of semantic cognition: converging evidence from neuropsychology, neuroimaging and TMS. | Recent studies suggest that a complex, distributed neural network underpins semantic cognition. This article reviews our contribution to this emerging picture and traces the putative roles of each region within this network. Neuropsychological studies indicate that semantic cognition draws on at least two interacting components: semantic representations [degraded in semantic dementia (SD)] and control processes [deficient in patients with multimodal semantic impairment following stroke aphasia (SA)]. To explore the first component, we employed distortion-corrected functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in healthy volunteers: these studies convergently indicated that the anterior temporal lobes (ATLs; atrophied in SD) combine information from different modalities within an amodal semantic "hub". Regions of cortex that code specific semantic features ("spokes") also make a critical contribution to knowledge within particular categories. This network of brain regions interacts with semantic control processes reliant on left inferior frontal gyrus (LIFG), posterior middle temporal gyrus (pMTG) and inferior parietal cortices. SA patients with damage to these regions have difficulty focussing on aspects of knowledge that are relevant to the current goal or context, in both verbal and non-verbal tasks. SA patients with LIFG and temporoparietal lesions show similar deficits of semantic control, suggesting that a large-scale distributed cortical network underpins semantic control. Convergent evidence is again provided by fMRI and TMS. We separately manipulated the representational and control demands of a semantic task in fMRI, and found a dissociation within the temporal lobe: ATL was sensitive to the number of meanings retrieved, while pMTG and LIFG showed effects of semantic selection. Moreover, TMS to LIFG and pMTG produced equal disruption of tasks tapping semantic control. The next challenges are to delineate the specific roles of each region within the semantic control network and to specify the way in which control processes interact with semantic representations to focus processing on relevant features of concepts. |
23260614 | Associations between gross motor coordination and academic achievement in elementary school children. | We aimed to evaluate the relationship between gross motor coordination (MC) and academic achievement (AA) in a sample of Portuguese children aged 9-12 years. The study took place during the 2009/2010 school year and involved 596 urban children (281 girls) from the north of Portugal. AA was assessed using the Portuguese Language and Mathematics National Exams. Gross MC was evaluated with the Körperkoordination Test für Kinder. Cardiorespiratory fitness was predicted by a maximal multistage 20-m shuttle-run test of the Fitnessgram Test Battery. Body weight and height were measured following standard procedures. Socio-economic status was based on annual family income. Logistic Regression was used to analyze the association of gross MC with AA. 51.6% of the sample exhibited MC disorders or MC insufficiency and none of the participants showed very good MC. In both genders, children with insufficient MC or MC disorders exhibited a higher probability of having low AA, compared with those with normal or good MC (p<.05 for trend for both) after adjusting for cardiorespiratory fitness, body mass index and socio-economic status. |
23260613 | Thigh pain, subsidence and survival using a short cementless femoral stem with pure metaphyseal fixation at minimum 9-year follow-up. | Short femoral stems designed to spare bone stock and improve load transfer at the proximal femur level have been introduced in recent years. However, little is known on the long-term outcomes of these stems. Short cementless stems have low rate of thigh pain and subsidence as well as few revision needs at mid-term follow-up. We prospectively followed 64 patients (72 hips) undergoing total hip arthroplasty with a femoral stem designed to achieve a pure metaphyseal fixation. Patients with hip fracture, femoral neck deformity and osteoporotic bone were excluded. Clinical evaluations were performed annually until the last follow-up, a minimum of 9 years after surgery. At each follow-up, implant positioning was assessed on conventional plain films with a computer assisted radiographic evaluation. The Harris hip score improved from 43 points (range 19-50) before surgery to 88 points (range 73-100) at the final follow-up (P=0.001), and the Womac score averaged 47 points (range 35-56 points) preoperatively and 76 points (range 63-84) at the last follow-up (P=0.001). Thigh pain was reported by five patients (8%) at the 2-year follow-up, but only in two (3%) was still present, and related to the prosthesis, at last follow-up. Computer assisted radiographic analysis showed a neutral alignment of the stem in 56% of cases, a varus-valgus alignment less than 5° in 36% and equal to 5° in 8%. Stem subsidence was observed in 12 hips but was less than 4mm in all cases (range 0-3mm). Calcar height remained unchanged over time. Adaptive bone remodelling, including proximal bone resorption and distal cortical hypertrophy were not observed at follow-up. No patients had aseptic loosening of the stem nor were radiolucent lines detectable at the level of the porous coating. Survivorship analysis showed a 100% survival rate of the stem at nine years. This study showed that a femoral stem designed to achieve a pure metaphyseal fixation may obtain, in a selected group of patients with adequate bone quality, satisfactory clinical outcomes without compromising implant stability. The limited periprosthetic bone remodelling observed after a minimum of 9 years follow-up suggests that this type of implant may improve mechanical stresses on host bone compared with standard stems requiring diaphyseal fixation. Level IV. Historical series. |
23260612 | The process associated with motivation of a home-based Wii Fit exercise program among sedentary African American women with systemic lupus erythematosus. | To explore the process associated with the motivation for playing Wii Fit among patients with systemic lupus erythematosus (SLE). Individual in-depth semi-structured telephone interviews were conducted with 14 sedentary African American women with SLE to explore their experiences and reflect on their motivation for playing Wii Fit after completing a 10-week home-based Wii Fit exercise program. Interviews were audio-recorded, transcribed verbatim, and analyzed using the constant comparative method to identify categories related to participants' motivation. Three authors independently sorted, organized and coded transcript text into categories, then combined the categories into themes and subthemes. In addition to the two themes (Ethical principal of keeping a commitment, and Don't want to let anyone down) generic to home-based exercise trials, we identified five themes (Enjoyment, Health Benefits, Sense of Accomplishment, Convenience, and Personalized) that revealed why the participants were motivated to play the Wii Fit. Enjoyment had three subthemes: Interactive, Challenging, and Competitive with an embedded social element. However, several participants commented they were not able to do many activities, master certain games, or figure out how to play some; as a result, they were bored with the limited selection of activities that they could do. The motivational elements of the Wii Fit may contribute to improved exercise motivation and adherence in select sedentary African American women with SLE. Results provide a better understanding on the important elements to incorporate in the development of sustainable home-based exercise programs with interactive health video games for this population. |
23260611 | Utahns' understanding of autism spectrum disorder. | The general public has numerous misconceptions and a lack of awareness and understanding regarding some of the prevalence, characteristics, and treatments of autism. As a result, education and awareness activities to increase the general public's understanding and awareness of autism are important. This study was conducted throughout Utah to inform public education and awareness efforts being planned as part of Utah's State Plan for Improving Outcomes for Individuals with Autism Spectrum Disorders and Development Disorders. The purpose of this study was to identify public awareness and knowledge of ASD in Utah, such as the public's understanding of the prevalence, characteristics, and treatments of autism, as well as the sources of this information. To identify public perceptions and attitudes of autism spectrum disorder, 1001 Utah residents 18 years of age or older were surveyed using a 32-question statewide random-digit dialed telephone survey. The percentages of responses for 15 of the 20 autism-related questions are presented by ethnicity (Hispanic or Latino), education level, and income level. The study indicates that autism education efforts need to address the least understood aspects of autism; the causes of autism, how autism is diagnosed, and how autism is treated. Radio or TV outlets are more effective, particularly so with Hispanic or Latinos and populations with less education. Medical professionals are also an important resource for families with direct autism-related needs. |
23260610 | Marital formation in individuals with work-related permanent impairment. | Prior studies on the impact of disabling work injury have neglected social support as a key mediating factor. This study investigates how permanent impairment from a work injury affects marital formation, an indicator of social support and integration with the potential to affect psychosocial adjustment and the resumption of productive social roles following work injury. Adjusting for socio-demographic and economic factors associated with marriage ability, we expect that individuals with a work-related permanent impairment will have a lower rate of marital formation compared to their non-injured counterparts. Drawing on a linkage of workers' compensation claims data with income tax information, we undertake a duration modeling analysis comparing workers who have sustained a workplace injury with a matched sample of non-injured controls to examine time to marital formation in each group. Women who suffered a disabling work injury were 17% less likely to marry relative to controls. High levels of physical impairment reduced the rate of marriage in women by 22%. We did not find an effect of impairment on marriage probability in models adjusted for income in men. Our findings underscore the importance of examining the social and interpersonal consequences of work injury, factors not currently addressed by the occupational rehabilitation system. |
23260609 | Receipt of mammography among women with intellectual disabilities: medical record data indicate substantial disparities for African American women. | Little information exists on the receipt of mammography by African American women with intellectual disabilities. Given the high rates of mortality from breast cancer among African American women and low screening rates among women with intellectual disabilities, it is important to understand the health screening behavior of this population. We compared rates of mammography receipt among African American and White women with intellectual disabilities (n = 92) living in community settings in one Southeastern state in the United States. Data were collected from women's medical records or abstraction forms obtained from medical practices. Multivariate logistic regressions were modeled for receipt of mammography in one year, one of two years, or both study years (2008- 2009). Covariates included the women's age, living arrangement, severity of impairment, and urban/rural residence location. In 2009, 29% of African American women and 59% of White women in the sample received mammograms. Similar disparities were found for receipt of mammography in either 2008 or 2009 and both 2008 and 2009. These disparities persisted after inclusion of model covariates. White women with intellectual disabilities received mammograms at adjusted rates that were nearly three to five times higher than African American women. African American women with intellectual disabilities receive mammography at significantly lower rates than White women with intellectual disabilities. Assertive measures to improve the screening rates for African American women with intellectual disabilities are urgently needed. |
23260608 | Tourette syndrome, parenting aggravation, and the contribution of co-occurring conditions among a nationally representative sample. | Previous research suggests that parents of a child with Tourette Syndrome (TS) have lower self-concepts, higher caregiver burden, and more difficulties with home activities. However, the contributions of TS and mental, emotional, or behavioral (MEB) conditions to family functioning are difficult to identify from previous research due to relatively small TS sample sizes and high rates of co-occurring conditions within samples of children with TS. The current study hypothesized that families of children with TS would report significantly more family functioning difficulties (more parenting aggravation, more difficulty with coping with the child's care, less parent-child communication, and less consistent family routines). Specifically, co-occurring conditions would contribute substantially to reported parenting aggravation. Parent-reported data from the 2007 National Survey of Children's Health were analyzed, including whether the child had been diagnosed with TS or an MEB. Weighted analyses were restricted to US children 6-17 years of age (n = 64,034) and adjusted for child age, sex, race and ethnicity. Parents of children with TS were more likely to fall into the high parenting aggravation index category compared with parents of children without TS (aPR = 3.8, 95% CI: 2.2-6.6). Controlling for the co-occurring MEB conditions attenuated the relations between TS and parenting aggravation; however, a significant effect for TS remained in some cases. Parents of children with TS may face significant challenges in raising their children, leading to increased parenting aggravation; these challenges appear to be primarily associated with the presence of co-occurring MEB conditions. |
23260607 | Satisfaction with healthcare services among Spanish people with disabilities. | Several studies show the relationship between patient satisfaction and quality of health services and also between disabling conditions and healthcare access, but none sufficiently analyze the factors that contribute to satisfaction among patients with disabilities. The primary aim of this paper is to quantify the impact of social factors, perceived health status and access on satisfaction with healthcare services among Spanish people with disabilities. This paper uses data from the European Health Survey 2009 to construct latent variables related to satisfaction, use and health status among Spanish patients with disabilities. Next, partial least squares path modeling is used for quantifying the effects of certain social factors, service use, and health status on patient satisfaction with received healthcare services. Satisfaction with healthcare services among people with disabilities is correlated (Nagelkerke R(2) of 0.175) with certain demographic factors (age, gender and town size), assistance support and patient use of these services. Education level and income were not found to have significant effects. People with disabilities generally show a high level of satisfaction with healthcare services, influenced by a positive valuation of the differentiated use given their specific care needs. Subjective aspects of care have a notable influence, linked with the perception of the person's own state of health and emotional status, on these positive valuations; patients' individual perceptions can reduce care needs and the use patients make of healthcare services and tend to increase their level of satisfaction with these services when they do seek them. |
23260606 | Evaluation of an activities of daily living scale for adolescents and adults with developmental disabilities. | Activity limitations are an important and useful dimension of disability, but there are few validated measures of activity limitations for adolescents and adults with developmental disabilities. To describe the development of the Waisman Activities of Daily Living (W-ADL) Scale for adolescents and adults with developmental disabilities, and systematically evaluate its measurement properties according to an established set of criteria. The W-ADL was administered among four longitudinally studied groups of adolescents and adults with developmental disabilities: 406 with autism; 147 with fragile-X syndrome; 169 with Down syndrome; and 292 with intellectual disability of other or unknown origin. The W-ADL contains 17 activities and each is rated on a 3-point scale (0 = "does not do at all", 1 = "does with help", 2 = "independent"), and a standard set of criteria were used to evaluate its measurement properties. Across the disability groups, Cronbach's alphas ranged from 0.88 to 0.94, and a single-factor structure was most parsimonious. The W-ADL was reliable over time, with weighted kappas between 0.92 and 0.93. Criterion and construct validity were supported through substantial associations with the Vineland Screener, need for respite services, caregiving burden, and competitive employment. No floor or ceiling effects were present. There were significant group differences in W-ADL scores by maternally reported level of intellectual disability (mild, moderate, severe, profound). The W-ADL exceeded the recommended threshold for each quality criterion the authors evaluated. This freely available tool is an efficient measure of activities of daily living for surveys and epidemiological research concerning adolescents and adults with developmental disabilities. |
23260605 | Reduction measures and percent body fat in individuals with intellectual disabilities: a scoping review. | Individuals with intellectual disability (ID) may be more obese and extremely obese than individuals without ID. There remains an on-going debate as to the effectiveness of exercise training in decreasing body fat in different populations. This scoping review explored the effects of exercise training interventions on percent body fat in individuals with ID. Authors conducted electronic searches through PubMED (1978 to present) and SPORT Discus (1975 to present) and evaluated relevant articles independently based on guidelines for scoping reviews. Few exercise interventions have targeted changes in percent body fat. Based on the 11 articles identified, exercise interventions appear effective at maintaining fat levels but have been largely unsuccessful at reducing body fat following training. Only 18% of exercise alone studies produced positive changes in body fat outcomes among individuals with ID. Greater focus should be placed on the metabolic health of individuals with ID. Results call into question methods used to date. These findings may be a consequence of the minimal attention paid to nutritional status and also a lack of standardized anthropometric methods and acceptable guidelines for categorizing adiposity based on health risk in this population. Further research is needed to promote more effective and sustainable strategies aimed at combating the elevated levels of body fat. |
23260601 | Phase I clinical trial of valacyclovir and standard of care cyclophosphamide in children with endemic Burkitt lymphoma in Malawi. | Treatment options for Epstein-Barr virus (EBV)-associated Burkitt lymphoma in Africa are limited because of chemotherapy-associated toxicity. Since other EBV-associated diseases respond to antiviral agents, we investigated adding an antiviral agent, valacyclovir, to the current chemotherapy regimen in Malawi. In this phase I safety study, we showed that cyclophosphamide combined with valacyclovir was safe. Phase II efficacy trials should now be undertaken. Nucleoside analogues, including acyclovir, ganciclovir, and their precursors, have shown some efficacy against several Epstein-Barr virus (EBV)-associated diseases, including active EBV infection and posttransplantation lymphoproliferative disorder (PTLD). They have also been proposed as a possible treatment for EBV-associated malignancies, including endemic Burkitt lymphoma. The safety of nucleoside analogues in combination with chemotherapy in the developing world has not been studied and is necessary before any large scale efficacy trials are conducted. Children 3-15 years old meeting inclusion criteria were assigned to a 3+3 dose escalation trial of combination valacyclovir (15 and 30 mg/kg, 3 times daily for 40 days) and cyclophosphamide (CPM) (40 mg/kg day 1, 60 mg/kg on days 8, 18, and 28) or CPM monotherapy. Subjects were monitored for clinical and laboratory toxicity and had EBV levels measured regularly. Dose-limiting toxicity (DLT) was our primary outcome. We found that the combination of valacyclovir and CPM was safe and did not lead to any DLT compared with CPM monotherapy. The most common side effects were vomiting, abdominal pain, and tumor site pain, which were similar in both arms. Patients with measurable serum EBV showed decreased loads over their treatment course. We recommend a phase II valacyclovir dose of 30 mg/kg 3 times daily for 40 days. We also observed that 6 of our 12 patients with presumed Burkitt lymphoma had measurable EBV viral loads that decreased over the course of their treatment, suggesting that phase II studies should investigate this correlation further. This study paves the way for a phase II efficacy trial of combined valacyclovir and CPM in the treatment of endemic Burkitt lymphoma. |
23260602 | Malnutrition and poor food intake are associated with prolonged hospital stay, frequent readmissions, and greater in-hospital mortality: results from the Nutrition Care Day Survey 2010. | The Australasian Nutrition Care Day Survey (ANCDS) ascertained if malnutrition and poor food intake are independent risk factors for health-related outcomes in Australian and New Zealand hospital patients. Phase 1 recorded nutritional status (Subjective Global Assessment) and 24-h food intake (0, 25, 50, 75, 100% intake). Outcomes data (Phase 2) were collected 90-days post-Phase 1 and included length of hospital stay (LOS), readmissions and in-hospital mortality. Of 3122 participants (47% females, 65 ± 18 years) from 56 hospitals, 32% were malnourished and 23% consumed ≤ 25% of the offered food. Malnourished patients had greater median LOS (15 days vs. 10 days, p < 0.0001) and readmissions rates (36% vs. 30%, p = 0.001). Median LOS for patients consuming ≤ 25% of the food was higher than those consuming ≤ 50% (13 vs. 11 days, p < 0.0001). The odds of 90-day in-hospital mortality were twice greater for malnourished patients (CI: 1.09-3.34, p = 0.023) and those consuming ≤ 25% of the offered food (CI: 1.13-3.51, p = 0.017), respectively. The ANCDS establishes that malnutrition and poor food intake are independently associated with in-hospital mortality in the Australian and New Zealand acute care setting. |
23260600 | Prognostic factors associated with disease progression and overall survival in patients with myelodysplastic syndromes treated with decitabine. | Decitabine improves overall survival (OS) and reduces risk of progression to acute myeloid leukemia (AML) in myelodysplastic syndromes (MDS). In this retrospective analysis of data from 2 decitabine studies (n = 162), hemoglobin level ≥ 10 g/dL, platelet count ≥ 50 10(3)/μL, and lack of chromosome 5 or 7 abnormalities predicted longer OS. Identifying potential prognostic factors for survival may guide decitabine treatment decisions and improve outcomes. Myelodysplastic syndromes (MDS) progress to acute myeloid leukemia (AML) in approximately 30% of patients. Identification of risk factors for progression to AML and overall survival (OS) would help guide treatment decisions. We investigated prognostic factors for progression to AML and survival in 163 patients with MDS treated with decitabine 15 mg/m(2) over 3 hours every 8 hours for 3 days every 6 weeks (n = 74) or 20 mg/m(2) over 1 hour daily for 5 days every 4 weeks (n = 89). Multivariate analysis of pooled baseline data revealed that only study effect was associated with progression to AML. A hemoglobin value at least 10 g/dL, platelet count at least 50 × 10(3)/μL, and lack of chromosome 5 or 7 abnormalities were associated with longer OS. Patients with certain prognostic factors should be considered for other interventions in addition to decitabine treatment. |
23260599 | High frequencies of response after limited primary therapy for multiple myeloma. | In an effort to maintain high primary response rates against multiple myeloma and without serious toxicity, we assessed 3 different bortezomib combinations in small numbers of patients, with combinations that included cyclophosphamide and lenalidomide in modest doses and for short courses. Remissions occurred in approximately 90% of patients, with rare episodes of serious drug-related adverse effects. Recent bortezomib combinations have induced remission in approximately 90% of patients newly diagnosed, with moderate frequency of adverse effects. In an attempt to reduce adverse effects, and to prepare qualified patients for early intensification, we assessed the antimyeloma effect and toxicity of 3 different bortezomib combinations in small numbers of patients. With reduced doses and short durations of exposure, we combined bortezomib with (a) cyclophosphamide/dexamethasone, (b) lenalidomide/dexamethasone/liposomal doxorubicin, and (c) cyclophosphamide/dexamethasone/lenalidomide. Response rates were high, with rare episodes of severe drug-related toxicity. Further study of similar combinations of effective drugs given in limited doses and for short durations would be useful. |
23260597 | The effect of vitrification on ultrastructure of human in vitro matured germinal vesicle oocytes. | To describe the possible effects of cryotop vitrification on maturation rate and ultrastructural morphology of human in vitro matured germinal vesicle (GV) oocytes. A total of 301surplus immature GV oocytes obtained from infertile patients were allocated into two groups: (i) GV oocytes (n=150) matured in vitro (fIVM), and (ii) GV oocytes (n=151) that were first vitrified, then matured in vitro (vIVM). Supernumerary fresh in vivo matured oocytes (n=10) were used as controls. The maturation media was Ham's F10 supplemented with FSH+LH and human follicular fluid. After 36h of incubation, the oocytes were investigated for nuclear maturation and ultrastructural changes using transmission electron microscopy (TEM). Oocyte maturation rates were reduced (P<0.001) in vIVM (45.92%) in comparison with fIVM oocytes (75.33%). The rate of degeneration was also significantly higher in vIVM than in the fIVM group (44.4% vs. 6.0%). Large and numerous mitochondria and minute vesicles of smooth endoplasmic reticulum (SER) complexes (MV complexes) were observed in both fIVM and vIVM groups. In addition, TEM revealed a drastic reduction in amount of cortical granules (CGs) at the cortex of vitrified-warmed GV oocytes, as well as appearance of vacuoles and small mitochondria-SER aggregates in the ooplasm. The vitrification procedure is associated with ultrastructural alterations in specific oocyte microdomains, presumably related to the reduced competence of cryopreserved oocytes for maturation. This information emphasizes the need for further work on advancing the cryotechnology of human oocytes. |
23260596 | Altered CD16 expression on vaginal neutrophils from women with vaginitis. | Reduced CD16 expression is associated with neutrophil apoptosis. This study aimed to compare CD16 expression on neutrophils in the vagina from women with normal bacterial flora and with vaginitis. Vaginal lavages were sampled from volunteers diagnosed with bacterial vaginosis (BV, n=34), vulvovaginal candidiasis (VC, n=43), BV plus VC (BV+VC, n=14), and normal flora (NF, n=51). Neutrophils were identified by expression of CD15, CD16 and CD24 surface markers as assessed by flow cytometry. CD16 expression was elevated in neutrophils from women with vaginitis (BV p<0.0001; VC p=0.01; BV+VC p=0.0027) as compared to women with NF. The reduction in CD16 down-regulation is consistent with prolonged neutrophil viability and activity in the vagina of women with vaginitis. This may contribute to greater microbial clearance and, conversely, with inflammation-associated pathology. |
23260578 | Exploration of 1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylurea derivatives as selective dual inhibitors of Raf1 and JNK1 kinases for anti-tumor treatment. | Based on the roles of Raf1 and JNK1 in hepatocarcinoma development, scaffold-based drug design was employed to produce a series of compounds, which subsequently were synthesized and explored as potential dual inhibitors Raf1 and JNK1 kinases for anti-tumor treatment. The compound 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chloro-phenyl)urea (3d) showed 66%, 67% and 13% inhibition rate at 50 μM against Raf1, JNK1 and p38-alpha, respectively, but no effect on ERK1 and ERK2, and inhibited the expression of pERK1/2 markedly and HepG2 cells proliferation with IC(50) at 8.3 μM. Furthermore, 3d showed lower toxicity against normal liver cell-lines QSG7701 and HL7702. Molecular docking study further showed that 3d can fit into binding domain of JNK1 and Raf1. Our data suggested the activities of 3d were associated with dual inhibition of JNK1 and Raf1 kinases. |
23260576 | Enhanced bioactivity of silybin B methylation products. | Flavonolignans from milk thistle (Silybum marianum) have been investigated for their cellular modulatory properties, including cancer chemoprevention and hepatoprotection, as an extract (silymarin), as partially purified mixtures (silibinin and isosilibinin), and as pure compounds (a series of seven isomers). One challenge with the use of these compounds in vivo is their relatively short half-life due to conjugation, particularly glucuronidation. In an attempt to generate analogues with improved in vivo properties, particularly reduced metabolic liability, a semi-synthetic series was prepared in which the hydroxy groups of silybin B were alkylated. A total of five methylated analogues of silybin B were synthesized using standard alkylation conditions (dimethyl sulfate and potassium carbonate in acetone), purified using preparative HPLC, and elucidated via spectroscopy and spectrometry. Of the five, one was monomethylated (3), one was dimethylated (4), two were trimethylated (2 and 6), and one was tetramethylated (5). The relative potency of all compounds was determined in a 72 h growth-inhibition assay against a panel of three prostate cancer cell lines (DU-145, PC-3, and LNCaP) and a human hepatoma cell line (Huh7.5.1) and compared to natural silybin B. Compounds also were evaluated for inhibition of both cytochrome P450 2C9 (CYP2C9) activity in human liver microsomes and hepatitis C virus infection in Huh7.5.1 cells. The monomethyl and dimethyl analogues were shown to have enhanced activity in terms of cytotoxicity, CYP2C9 inhibitory potency, and antiviral activity (up to 6-fold increased potency) compared to the parent compound, silybin B. In total, these data suggested that methylation of flavonolignans can increase bioactivity. |
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